Conditions: Drug Drug Interaction
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 28
Healthy volunteers: yes

Brief summary:
An open label, balanced, randomized, single-dose, two-treatment, two-sequence, two-period, crossover oral drug-drug interaction study of spironolactone (perpetrator) and Digoxin (substrate drug) in healthy adult human subjects under fasting condition.

Detailed description:
Drug interaction studies between spironolactone and digoxin, particularly studies in which digoxin was administered intravenously (Waldorf, S 1978; Fenster, P.E. 1984), indicate that spironolactone may decrease the renal clearance of digoxin by 18-25%, and increase the (area under curve) AUC of digoxin by 35-44%. Although the radioimmunoassay used in the study may be confounded, these results suggest that inhibition of P-gp in the renal proximal tubules may be possible. To account for possible renal P-gp inhibition, subjects in the test group will be pretreated with spironolactone for about 5 days to allow accumulation of some of the metabolites which have a long half-life (e.g., canrenone \~33 hours) and continue to be treated with spironolactone while digoxin is renally eliminated from the body. Based on this assessment, the FDA suggested study design is Treatment A: Single dose of digoxin alone. Treatment B: Digoxin + Spironolactone; Day 1- 9: Spironolactone single dose; Day 6: Digoxin single oral dose.

Also, digoxin has a long half-life of 1.5-2 days, and the Pharmacokinetic (PK) sampling scheme of up to 72 hours may not be enough to characterize the elimination kinetics of digoxin. Hence, the plasma concentrations of digoxin up to 96 hours (4 days) postdose is considered This will allow you to detect possible differences in the clearance of digoxin mediated by an interaction with P-gp in the renal proximal tubules.

The study also involves collecting urine samples and measuring renal clearance (CLR) and unchanged drug excreted in urine (fe) for digoxin.

Arms:
arm 1: 14 Subjects first administered with LANOXIN® (digoxin) USP 250 mcg (Substrate drug) on Day 6 of in house, after overnight fasting of at least 10.00 hours.

After washout period of 28 days, these 14 subjects were administered with Spironolactone Oral Suspension 100 mg (perpetrator, Carospir® Oral Suspension 20 mL of 25 mg / 5 mL) from day 1 to day 5 and on day 6 the after overnight fasting of at least 10.00 hours, subject was administered with LANOXIN® (digoxin) USP 250 mcg (substrate drug) + Spironolactone Oral Suspension 100 mg (perpetrator; Carospir® Oral Suspension 20 mL of 25 mg / 5 mL). From day 7 to day 9 the subjects were administered with Spironolactone Oral Suspension 100 mg (perpetrator; Carospir® Oral Suspension 20 mL of 25 mg / 5 mL). arm 2: 14 Subjects first administered with Spironolactone Oral Suspension 100 mg (perpetrator, Carospir® Oral Suspension 20 mL of 25 mg / 5 mL) from day 1 to day 5 and on day 6 the after overnight fasting of at least 10.00 hours, subject was administered with LANOXIN® (digoxin) USP 250 mcg (substrate drug) + Spironolactone Oral Suspension 100 mg (perpetrator; Carospir® Oral Suspension 20 mL of 25 mg / 5 mL). From day 7 to day 9 the subjects were administered with Spironolactone Oral Suspension 100 mg (perpetrator; Carospir® Oral Suspension 20 mL of 25 mg / 5 mL).

After washout period of 28 days these 14 Subjects administered with LANOXIN® (digoxin) USP 250 mcg (Substrate drug) on Day 6 of in house, after overnight fasting of at least 10.00 hours

Interventions: intervention 1: Digoxin 250 MCG Oral Tablet intervention 2: Spironolactone 25 mg/ 5 mL S/F Suspension
Intervention descriptions: intervention 1: The intervention is for study of drug drug interaction of digoxin when administered with spironolactone oral suspension intervention 2: The intervention is for study of drug drug interaction of digoxin when administered with spironolactone oral suspension

Protocol document:
Prot_000.pdf: 
Clinical Study Repo11 for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Conlidential 
CLINICAL STUDY REPORT 
l. 
TITLE PAGE 
Study title 
An open label, balanced, randomized, single-dose, two-
treatment, two-sequence, two-period, crossover oral drug-drug 
interaction study of spironolactone (perpetrator) and Digoxin 
(substrate drug) in healthy adult human subjects under fasting 
condition. 
LANOX!N® (digoxin) USP 250 meg (substrate drug), 
Treatment (A) 
manufactured 
for 
Concordia Pharmaceuticals Inc., 
St. 
Michael, Barbados BB 11005. Initial U.S 
LANOXIN® (digoxin) USP 250 meg (substrate drug) + 
Treatment (B) 
Spironolactone Oral 
Suspension 
I 00 
mg (Perpetrator; 
Carospir® Oral Suspension 20 mL of 25 mg I 5 mL of CMP 
Development LLC, USA.) 
Indication studied 
Not Applicable 
An open label, balanced, randomized, single-dose, two-
Study design 
treatment, two-sequence, two-period, crossover, drug-drug 
interaction study in healthy adult human subjects under 
fasting condition. 
Name of the sponsor 
CMP Development, LLC. 
Protocol No. 
C-CMP-SPI-00 I 
Development phase of 
Drug-Drug interaction study 
study 
Study start date 
10 Mar 2019 
Study end date 
17 Apr 2019 (last blood sample collection of the study) 
Principal Investigator 
Dr. P. Venkatesh, MBBS, Ph.D 
Clinical Pharmacology Department, 
ClinSync Clinical Research Pvt. Ltd., 
JSR Mall, Plot No.7 to 18, Madinaguda 
Village, Serilingampally Mandai, 
Hyderabad-500050, 
Telangana, India 
Phone No.: 040-29887005/06 
Email!D: venkatesh.p@clinsynccro.com 
Protocol No. C-CMP-SPI-001 
Confidential 
Page I of64 


Clinical Study Report J(Jr Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Sponsor's 
Representative 
Gerald Sakowski 
Chief Executive Of1icer 
CMP Development LLC 
PO Box 147 
8026 US Highway 264A 
I 
Farmville, NC 27828 
Telephone: (800)227-6637 
Confidential 
-------------+-
------------------------------
Version 
01 
~ Date of study repo~t 
- Ol-Jul 20 I 9-------------------
[ 
This study was performed according to the protocol and in compliance with Good 
.1 
Clinical Practices (GCP) and Good Laboratory Practices (GLP) 
~ 
Protocol No. C-CMP-SPJ-00 I 
Confidential 
Page 2 of 64 


Clinical Study Report f(lr Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
2. 
SYNOPSIS 
I Name of Sponsor I 
Company: 
CMP Development 
I LLC 
I Name of Finished 
Products: 
Digoxin USP 250 meg + 
Spironolactone suspension 
, 100 mg (20 mL of25 mg I 5 
mL) 
Name of Active 
Ingredients: 
Digoxin 
Title of Study 
Investigators 
Protocol No. C-CMP-SPI-001 
Contidcntial 
I Individual Study Table 
Referriug to Part of 
the Dossier 
- (Fm:Natio11al Authority -l 
Use o111)') 
Volume: 
Page: 
An open label, balanced, randomized, single-dose, two-
treatment, two-sequence, two-period, crossover oral drug-
drug interaction study of spironolactone (perpetrator) and 
Digoxin (substrate drug) in healthy adult human subjects 
under fasting condition. 
Principal Investigator: 
Dr. P. Venkatesh, MBBS 
Sub Investigator: 
Dr. Sreedhar Reddy Peddi, MD General Medicine, 
DNB (cardiology) 
Clinical Investigator: 
Dr. S. Ravikishore, MBBS 
Bioanalytical Investigator: 
Mr. Praveen Rao M, M. Sc., 
Pharmacokinetic Investigator: 
Dr. Jaganmohan S, Ph.D, PDF 
Statistical Investigator: 
Mr. Tushar Shinde, M. Sc 
Note: 
Dr. 
P.Venkatesh 
handed 
over his 
Principal 
Investigator resposibilities to Dr.S.Ravikishore on Period I 
check-in day due to his personal reasons and the same 
I information was notified to EC and sponsor. For Period II, I 
Contidential 
Page 3 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
subsequent follow up and approval of has been done by 
Dr. Venkatesh 
as 
study 
Principal 
Investigator. 
This 
information is also applicable to the section 6.0 
Study Center 
ClinSync Clinical Research Pvt. Ltd., 
Clinical Pharmacology Department, 
JSR Mall, Plot No.7 to I 8, 
Madinaguda Village, Serilingampally Mandai, 
Hyderabad-500050, Telangana, India 
Phone No.: 040-29887005/06 
Publication (reference) 
Not Applicable 
Bioanalytical, 
ClinSync Clinical Research Pvt. Ltd., 
Pharmacokinetic 
Clinical Pharmacology Department, 
and Statistical Facility 
JSR Mall, Plot No.7 to 18, 
Madinaguda Village, Serilingampally Mandai, 
Hyderabad-500050, Telangana, India 
Phone No.: 040-29887005/06 
Clinical start date 
10 Mar 2019 
Clinical end date 
I 7 Apr 2019 (last blood sample collection ofthe study) 
Bioanalytical analysis start Plasma 23 Apr 2019 
date 
Urine 
24 May 2019 
Bioanalytical analysis end Plasma 04 May 2019 
date 
Urine 
04 Jun 2019 
Statistical analysis start 
07Jun2019 
date 
Statistical analysis end date 
IOJun 2019 
Phase of development 
Drug-Drug interaction study 
Objectives 
Primary Objective: 
To characterize the pharmacokinetic profile of Digoxin 
(substrate drug) 
111 
the presence and 
absence of 
spironolactone (perpetrator) in 
healthy adult human 
subjects under fasting condition. 
Secondary Objectives: 
• To assess whether there is a drug-drug interaction with 
Protocol No. C-CMP-SPI-001 
Confidential 
Page 4 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Methodology 
Protocol No. C-CMP-SPI-001 
Confidential 
concomitant use of spironolactone. 
• To measure renal clearance (CLR)/Percent Recovered 
and unchanged drug excreted m urine (fe)l Amount 
Recovered for digoxin in the presence and absence of 
spironolactone (perpetrator) m healthy adult human 
subjects under fasting condition. 
• To monitor safety of the subjects in drug-drug interaction 
study. 
This was an open label, balanced, randomized, single-dose, 
two-treatment, 
two-sequence, 
two-period, 
crossover, 
drug-drug interaction study in healthy adult human subjects 
with at least 28 days washout period between each 
treatment period under fasting condition. 
In both periods (Period-! and II), from Day I to Day 5 and 
Day 7 to Day 9, the subjects who were randomized to 
treatment B, were administered Spironolactone Oral 
Suspension 
I 00 
mg 
(Perpetrator; 
Carospir® 
Oral 
Suspension 20 mL of 25 mg I 5 mL), and the subject who 
were randomized to treatment A were not dosed. On all 
these days the standard breakfast was served 0.50 hr (30 
min) post dose. On Day 6, after overnight fasting for at 
least I 0.00 hours the subjects were dosed either with the 
Treatment (A) [LANOXIN® (digoxin) USP 250 meg 
(substrate drug)] or Treatment (B) [LANOXIN® (digoxin) 
USP 250 meg (substrate drug) + Spironolactone Oral 
Suspension 
I 00 
mg 
(Perpetrator; 
Carospir® 
Oral 
Suspension 20 mL of 25 mg I 5 mL)] as per the 
randomization scheme. 
Urine & Blood samples collection were collected after the 
completion of dosing on Day 6. 
Urine samples 
A total of II urine samples were collected from each 
subject in each study period at intervals of (0.00-1.00), 
(1.00-2.00), (2.00-4.00), (4.00-6.00), (6.00-8.00), (8.00-
12.00), 
(12.00-16.00), 
(16.00-24.00), 
(24.00-48.00), 
( 48.00-72.00) and (72.00-96.00) hours post dose. 
Immediately out of the total volume of urine collected at 
each collection time interval, approximately I 0 mL (2 x 5 
mL aliquots) of urine samples were transferred into two 
I pre-labeled containers for analysis and stored at deep 
Confidential 
Page 5 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Protocol No. C-CMP-SPI-001 
Confidential 
freezer maintained at -20°C or lower until dispatched from 
Clinical Unit to Bioanalytical Department for analysis. 
After collecting the urine samples from all the subjects at 
each collection time interval, the total pooled volume was 
recorded and transferred to analytical site for analysis after 
the completion of clinical phase. 
Blood samples 
A total of25 (I x 5 mL) blood samples were collected from 
each subject in each study period at pre-dose (0.00) and at 
0.25, 0.50, 0.75, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 
3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00, 24.00, 
36.00, 48.00, 60.00, 72.00 and 96.00 hours post dose. 
Note: Blood samples up to 3 hours post dose were 
collected at bed side. 
The pre and post-dose blood samples up to 24.00 hrs were 
collected via an indwelling cannula and 36.00, 48.00, 
60.00, 72.00, and 96.00 post dose samples were collected 
by a fresh vein-puncture. 
The pre-dose blood sample were collected within 2 hours 
before dosing and the post-dose in-house samples were 
collected with a window period of + 2 minutes from the 
scheduled sampling time. 
The collected blood samples were kept on ice-packs until 
centrifugation. All the samples except 0.25 hr sample in 
period I, were centrifuged within 45 minutes from the 
scheduled blood sample collection. The samples were 
centrifuged at the set conditions of 4000 rpm for 10 
minutes at 4 °C to separate plasma. The separated plasma 
was transferred to pre-labeled polypropylene tubes in two 
equal aliquots. 
The total amount of blood collected from each subject 
during the study was about 292 mL 
Subjects were abstained from consuming any alcoholic 
products from 48.00 hours prior to check-in to till 
check-out /last sample of the study. They were not allowed 
to have any xanthine-containing food and/or beverages 
(like chocolate, tea, coffee, cola drinks), cigarettes and 
tobacco containing products and grapefruit and/or it's juice 
from 48.00 hours prior to check-in to till check-out I last 
sample of the study. 
Confidential 
Page 6 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
On Day 6, subjects were fasted for at least I 0.00 hours 
prior to dosing. 
Water was provided ad libitum during the study, except one 
hour before and one hour after dosing on Day 6. 
On Day 6, subjects who are dosed remained in a supine 
position or semi recumbent position for 03 hours post-dose 
and only necessary movement was allowed during this 
period. Thereafter subject was allowed to ambulate freely 
during the remaining part of the study. Subject did not 
sit down (except as directed by the physician secondary to 
adverse events) during restriction period. 
Number of subjects 
• No. of subjects planned: 28 + 04 (standby subjects) 
• No. of subjects randomized: 28 
• No. of subjects dosed in period I: 28 
• No. of subjects dosed in period II: 28 
• No. of subjects withdrawn: 00 
• No. of subjects dropped out: 00 
• No. of subjects completed the study: 28 
• No. of subjects analyzed in bioanalytical facility: 28 
• No . of subjects analyzed for pharmacokinetic and 
statistical analysis: 28 
Diagnosis and main criteria Healthy consenting human adult subjects between 20 and 
for inclusion 
35 years of age (both ages inclusive), of Body Mass Index 
(BMI) within 18.5 to 24.9 Kg/ m2 with normal laboratory 
measurements were included in the study. Subjects 
weighing less than 60 kg were not enrolled. 
Treatment (A) 
LANOXIN® (digoxin) USP 250 meg (substrate drug), 
manufactured for Concordia Pharmaceuticals Inc., St. 
Michael, Barbados BBII005. Initial U.S 
LANOXIN® USP 250 meg 
AH3690B 
Lot No. 
Dose and mode of 
Single oral dose administered with 120 mL of water under 
administration 
fasting condition. 
Treatment (B) 
LANOXIN® (digoxin) USP 250 meg (substrate drug) 
manufactured for Concordia Pharmaceuticals Inc., St. 
Michael, Barbados BBIJ005. Initial U.S+ Spironolactone 
Oral Suspension 100 mg (Perpetrator; Carospir® Oral 
Protocol No. C-CMP-SPI-001 
Confidential 
Page 7 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
Suspension 20 mL of 25 mg I 5 mL of CMP Development 
LLC, USA) 
(Carospir@ Oral 
1118211 
Suspension) Lot No. 
Dose and mode of 
In case of subjects who were assigned Treatment A, Single 
administration 
oral dose of LANOXIN@ (digoxin) USP 250 meg was 
administered with 240 ± 2 mL of water under fasting 
condition. Subjects swallowed the tablet as a whole. 
Dosing compliance was assessed by oral cavity check. 
In case of subjects who were assigned Treatment B, single 
oral dose of LANOXIN@ (digoxin) USP 250 meg was 
administered with 120 mL of water under fasting condition 
and Carospir@ Oral Suspension I 00 mg (20 mL of 25 mg I 
5 mL) was administered with 120 mL of water with a 
graduated syringe. Dosing activity was done under the 
supervision of cardiologist. 
CaroSJ)ir oral susgension administration grocedure 
20 mL of 25 mg I 5 mL of Carospir® Oral Suspension was 
loaded in the syringes well in advance prior to dosing on 
the day of dosing. The suspension in the syringe was 
directly administered to the subjects. Then the syringe was 
rinsed with approximately 10 mL from 120 mL of dosing 
water and administered to the subjects. This rmsmg 
procedure was done until the syringe was free of the 
contents of the medication. Then the remaining quantity of 
water from the assigned 120 ml water was finally 
administered to the subjects. 
Duration ofthe treatment 
A 
single 
oral 
dose of Carospir® 
100 
mg 
Oral 
(Spironolactone 20 mL of 25 mg I 5 mL) suspension from 
Day I to Day 5 and Day 7 to Day 9 and on Day 6 either 
LANOXIN® (digoxin) USP 250 meg (substrate drug) or 
LANOXIN® (digoxin) USP 250 meg (substrate drug) + 
Carospir® I 00 mg Oral (Spironolactone 20 mL of 25 mg I 5 
mL) suspension (Perpetrator) were administered on 
II Mar 2019 and 08 Apr 2019 in period I and period II, 
respectively separated by a washout period of 28 days. 
Total duration of the study from the check in of period I to 
the last blood draw of period II did not exceed 39 days. 
Criteria for evaluation: 
Subjects were monitored for safety and tolerability during 
Safety Evaluation 
the entire study. The subject's Clinical examination along 
Protocol No. C-CMP-SPI-001 
Confidential 
Page 8 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Pharmacokinetic 
Evaluation 
Statistical Evaluation 
Protocol No. C-CMP-SPI-001 
Confidential 
with vital signs (seated blood pressure, radial pulse rate and 
oral/aural temperature) were measured during check-in and 
check-out of each period. 
Clinical examination was done on prior to dosing on Day 
06 in each study period. 
Oral/aural temperature was measured prior to dosing in 
each study period. 
Vital parameters - seated blood pressure and radial pulse 
rate were measured at prior to dosing, 1.00, 3.00, 5.00 and 
11.00 hours post dose in each period from Day 1 to Day 5, 
and from Day 6 to Day 9, vitals were measured prior to 
dosing, at 1.00, 2.00, 3.00, 5.00, 8.00 and 11.00 hours post 
dose in each period. 
Note 
• 
On Day 6 the Vital signs (i.e. up to 3.00 hours post 
dose) was performed at bed side. 
• 
For subjects who were randomized to treatment A, the 
vitals were checked at 5.00 hours post dose during day 
1 to Day 5. 
ECG was performed at 1.00 and 3.00 hours post dose in 
each period on Day 6, before period 11 check-in for subject 
study eligibility and at check-out of each period of the 
study. 2D echo was performed at the time of screening. 
In each study period subject's creatinine clearance and 
serum potassium levels were measured on Day 5 for the 
dosing eligibility on Day 6. 
For the safety of the subjects, hematology (except blood 
grouping and Rh typing) and biochemistry (except random 
blood sugar) investigations were repeated at the end of the 
study. 
The following pharmacokinetic parameters for Digoxin 
were 
obtained 
using 
non-compartmental 
method 
(WinNonlin, version 8.1, Pharsight Corporation, USA): 
>-
Cmax. AUCo.96, and tmax using plasma data, 
>-
Renal clearance (CLR) /Percent Recovered, Unchanged 
drug excreted in urine (fe)/Amount Recovered using 
urine data. 
The log-transformed pharmacokinetic parameters Cmax and 
AUC0.96 were analysed using Type Ill sum of squares, with 
Confidential 
Page 9 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
the mam etTects of formulation, period, sequence and 
subjects nested within sequence as random effect. 
Statistical analysis was performed using SAS<R package 
(SAS Institute Inc., USA, Version 9.3). 
The presence or absence of DDI between the two 
treatments (A and B) was concluded based on the statistical 
results of 90% confidence interval for the ratio of the 
geometric 
least 
squares 
mean 
for 
log-transformed 
pharmacokinetic parameters Cmax and A UC0.96 for Digoxin. 
Absence of drug-drug interaction would be established if 
the 90% Cl for the ratio of population geometric means of 
log-transformed data of Cmax and AUC0.96 between two 
treatments (A and B), were in the equivalence limits of 
80.00 - I 25.00% for Digoxin. 
Summary and Conclusions 
Pharmacokinetic & Statistical Results: 
Table 1: Summary of Plasma Pharmacokinetic parameters for digoxin- Treatment (A) 
Treatment 
Product/Statistics 
Cm,.(nglmL) 
Au c .. ,. (ng.hr/mL) 
T m" (hr) 
N 
28 
28 
28 
Mean 
1530.188 
13715.974 
0.744 
SD 
502.810 
2669.003 
0.195 
Treatment 
Min 
644.613 
8632.172 
0.500 
(A) 
Median 
1429.822 
13440.345 
0.750 
Max 
2734.608 
21455.761 
1.330 
Geometric Mean 
1456.085 
13473.043 
0.721 
CV% Geometric Mean 
32.993 
19.431 
25.996 
Table 2: Summary of Plasma Pharmacokinetic parameters for digoxin- Treatment (B) 
Treatment 
Product/Statistics 
Cm, (nglmL) 
AUC0.,. (ng.hr/mL) 
T mn(hr) 
N 
28 
28 
28 
Mean 
2432.908 
16551.500 
0.901 
SD 
870.562 
4108.500 
0.569 
Min 
539.707 
6373.657 
0.500 
Treatment (B) Median 
2422.385 
17151.091 
0.750 
Max 
5044.130 
23997.624 
3.500 
Geometric Mean 
2254.118 
15996.644 
0.810 
CV% Geometric Mean 
45.789 
28.453 
44.310 
Protocol No. C-CMP-SPI-001 
Confidential 
Page 10 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
Table 3: Ratio and 90% Confidence Intervals of Treatment (A) versus Treatment (B) for 
digoxin 
Geometric Least Square Means and It's Ratio 
PK Parameters 
(Treatment A I 
90%CI 
Power 
ISCV 
(Unit) 
Treatment A Treatment B 
Treatment B) 
(%) 
(%) 
(%) 
LOG Cmax 
1456.085 
2254.118 
I 
64.597 
40.07 
54.18% to 
67.47 
(ng/mL) 
~-~~-~~~~-~ 
77.02% 
LOG AUCo-96 
13473.043 
15996.644 
84.224 
18.56 
77.45%10 
99.56 
(ng.hr/mL) 
-~--
i 
' 
91.59% 
- -
Table 4: Summary of Urine Pharmacokinetic parameters for digoxin- Treatment (A) 
Renal clearance 
unchanged drug excreted in 
Treatment 
Product/Statistics 
(CLR)/Percent 
Recovered 
urine (fe)/ Amount Recovered 
N 
28 
28 
Mean 
54.687 
!36717.72 
SD 
29.158 
72895.492 
Treatment A 
Min 
22.180 
55449.800 
Median 
46.111 
115277.98 
Max 
147.642 
369104.30 
G. Mean 
49.042 
122606.02 
G.mean%CV 
48.257 
48.257 
Table 5: Summary of Urine Pharmacokinetic parameters for digoxin- Treatment (B) 
Renal clearance 
unchanged drug excreted in 
Treatment 
Product/Statistics 
(CLR)/Percent 
Recovered 
urine (fe)/ Amount Recovered 
N 
28 
28 
Mean 
53.378 
133446.07 
SD 
21.256 
53141.044 
TreatmentB 
Min 
21.641 
54103.200 
Median 
51.185 
127962.08 
Max 
95.602 
239003.90 
G. Mean 
49.410 
123523.87 
G.mean%CV 
42.201 
42.201 
Safety Res nits 
There were no adverse events recorded during the study. 
Therefore, the safety of the digoxin in the presence and 
absence of spironolactone would 
be 
considered 
as 
comparable. 
Protocol No. C-CMP-SPI-001 
Confidential 
Page II of64 


Clinical Study Report lt1r Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
I Conclusion 
Conlidential 
The exposure (C,, and AUC0_91,) of digoxin was not 
comparable for the Treatment A and Treatment 8_ The 
geometric mean l,,." was 1456.085 and 2254.118 ng/mL for 
Treatment A and Treatment B respectively. The geometric 
mean AUC0_96 was 13473.043 and 15996.644 ng.hr/mL f(Jr 
Treatment A and Treatment B respectively 
By comparing C,,." and AUCo-96 plasma values of 
Treatment A and Treatment B, we conclude that these 
values were increased by 35% and 16% respectively for 
Treatment B. 
The %Treatment A/Treatment B ratio of digoxin was 
64.597% and 84.224% for C,, and AUC0_96 respectively. 
The lower and the upper limits at 90% confidence interval 
were 54.18% - 77.02% and 77.45% - 91.59% for C,"' and 
AUCo_96 respectively, which were not within the standard 
equivalence limit of 80.00-125.00%. Based on the above 
results presence of drug-drug interaction is established 
between digoxin and spironolactone. 
The 
Renal 
clearance 
(CLR)/Percent 
Recovered 
and 
unchanged drug excreted in urine (fe)/ Amount Recovered 
of digoxin was comparable for the Treatment A and 
Treatment B. 
The geometric mean Renal clearance 
(CLR)/Percent Recovered was 49.042 and 49.410 for 
Treatment A and Treatment B respectively. The geometric 
mean unchanged drug excreted in urine (fe)/ Amount 
Recovered was 122606.02 and 123523.87 for Treatment A 
and Treatment B respectively. By comparing these values, 
we conclude that there is not much difference between 
Treatment A and Treatment B, with respect to Renal 
clearance (CLR)/Percent Recovered and unchanged drug 
excreted in urine (fe )I Amount Recovered. 
r--------·-··------~--- -------------------··· 
--
DATEOFTHEREPORT 
01 Jul2019 
Protocol No. C-CMP-SPI-001 
Confidential 
Page 12 of 64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
3. 
TABLE OF CONTENTS 
I. TITLE PAGE ....................................................................................................................... I 
2. SYNOPSIS .......................................................................................................................... 3 
3. TABLE OF CONTENTS .................................................................................................. 13 
4. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... .20 
5. ETHICS ............................................................................................................................. 22 
5.1 
INSTITUTIONAL ETHICS COMMITTEE (IEC) ..................................................... 22 
5.2 
ETHICAL CONDUCT OF THE STUDY ................................................................... 22 
5.3 
SUBJECT INFORMATION AND CONSENT .......................................................... 23 
6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................ 24 
7. INTRODUCTION ............................................................................................................. 26 
8. STUDY OBJECTIVES ..................................................................................................... 27 
9. INVESTIGATIONAL PLAN ............................................................................................ 28 
9.1 
OVERALL STUDY DESIGN AND PLAN- DESCRIPTION .................................. 28 
9.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL 
GROUPS ...................................................................................................................... 29 
9.3 
SELECTION OF STUDY POPULATION ................................................................. 29 
9.3.1 Inclusion Criteria ................................................................................................ 29 
9.3.2 Exclusion Criteria .............................................................................................. .30 
9.3.3 Removal of Subjects from Study or Assessment.. ............................................. .31 
9.4 
TREATMENTS ........................................................................................................... 31 
9.4.1 Treatments Administered .................................................................................... 31 
9.4.2 Identity of Investigational Products .................................................................... 32 
9.4.3 Method of Assigning Subjects to Treatment Groups ........................................ .33 
9.4.4 Selection of Doses in the Study .......................................................................... 34 
9.4.5 Selection and Timing of Dose for each Subject ................................................ .34 
9.4.6 Blinding ............................................................................................................. .36 
9.4.7 Prior and Concomitant Therapy .......................................................................... 36 
9.4.8 Treatment Compliance ........................................................................................ 36 
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9.5 
EFFICACY AND SAFETY VARIABLES ................................................................. 36 
9.5.1 Pharmacokinetic and Safety Measurements Assessed ....................................... 36 
9.5.2 Appropriateness of Measurements .................................................................... .37 
9.5.3 Primary Pharmacokinetic Variable(s) ................................................................ .37 
9.5.4 Drug Concentration Measurements .................................................................... 38 
9.6 
DATA QUALITY ASSURANCE ............................................................................... 39 
9.7 
STATISTICAL 
METHODS 
PLANNED 
IN 
THE 
PROTOCOL 
AND 
DETERMINATION OF SAMPLE SIZE .................................................................... 39 
9.7.1 Statistical and Analytical Plans .......................................................................... 39 
9.7.2 Determination of Sample Size ........................................................................... .41 
9.8 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANAL YSES .. .41 
I 0. STUDY SUBJECTS .......................................................................................................... 42 
I 0.1 DISPOSITION OF SUBJECTS .................................................................................. 42 
I 0.2 PROTOCOL DEVIATIONS ...................................................................................... .42 
II. PHARMACOKINETIC EVALUATION .......................................................................... 43 
II. I DATA SETS ANALYSED ........................................................................................ .43 
11.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERJSTICS ..................... .43 
11.3 MEASUREMENTS OF TREATMENTS COMPLIANCE ....................................... .43 
11.4 PHARMACOKINETIC RESULTS AND TABULATIONS OF INDIVIDUAL 
SUBJECT DATA ........................................................................................................ 44 
11.4.1 Pharmacokinetic & Statistical Analysis .............................................................. 44 
11.4.2 Statistical I Analysis lssues ................................................................................. 48 
11.4.3 Tabulation oflndividual Response Data ............................................................ 49 
11.4.4 Drug Dose, Drug Concentration, and Relationships to Response ...................... 49 
11.4.5 Drug-Drug and Drug-Disease Interactions ......................................................... 49 
11.4.6By- Subject Displays ........................................................................................ .49 
11.4. 7 Pharmacokinetic Conclusions ............................................................................. 49 
12. SAFETY EVALUATION ................................................................................................. 51 
12.1 EXTENT OF EXPOSURE .......................................................................................... 51 
12.2 ADVERSE EVENTS (AEs) ........................................................................................ 51 
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12.2.1 Brief summary of adverse events ....................................................................... 51 
12.2.2 Display of adverse events ................................................................................... 51 
12.2.3 Analysis of Adverse Events ................................................................................ 51 
12.2.4 Listing of Adverse Events by Subject ................................................................ 51 
12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT 
ADVERSE EVENTS ................................................................................................... 51 
12.3.1 Listing of Deaths, other Serious Adverse Events and Other Significant Adverse 
Events 51 
12.3.1.1 Deaths ............................................................................................................ 51 
12.3.1.2 Other Serious Adverse Events ....................................................................... 52 
12.3.1.3 Other Significant Adverse Events ................................................................ .52 
12.3.2 Narratives of Deaths, Other Serious Adverse Events and Certain Other 
Significant Adverse Events .......................................................................................... 52 
12.3.3Analysis and Discussion of Deaths, Other Serious Adverse Events and Other 
Significant Adverse Events .......................................................................................... 52 
12.4 CLINICAL LABORATORY EVALUATION ........................................................... 52 
12.4.1 Listing ofindividual Laboratory Measurements by Subject .............................. 52 
12.4.2 Evaluation of Laboratory Parameter ................................................................... 52 
12.5 VITAL SIGNS, PHYSICAL FINDINGS AND 
OTHER OBSERVATIONS 
RELATED TO SAFETY ............................................................................................. 52 
12.6 SAFETY CONCLUSIONS ......................................................................................... 53 
13. DISCUSSION AND OVERALL CONCLUSIONS ......................................................... 54 
14. TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE 
TEXT ....................................................................................................................................... 56 
14.1 DEMOGRAPHIC DATA ............................................................................................ 56 
14.2 PHARMACOKINETIC DATA ................................................................................... 57 
14.3 SAFETYDATA .......................................................................................................... 61 
14.3.1 Displays of Adverse Events ................................................................................ 61 
14.3.2Listing of Deaths, Other Serious and Significant Adverse Events ..................... 61 
14.3.3Narratives of Deaths, Other Serious and Certain Other Significant Adverse 
Events 61 
14.3.4Abnormal Laboratory Value Listing (each Subject) .......................................... 61 
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15. REFERENCE LIST ........................................................................................................... 62 
16. APPENDICES ................................................................................................................... 63 
16.1 STUDY INFORMATION ........................................................................................... 63 
16.1.1 Protocol and Protocol Amendments ................................................................... 63 
16.1.2 Sample case report form ..................................................................................... 63 
16.1.3 List of IEC members along with approval letter- Representative written 
information for subject and sample informed consent documents .............................. 63 
16.1.4 List and description of investigators and other important participants in the 
study, including briefCVs or equivalent summaries of training and experience 
relevant to the performance of the clinical study ......................................................... 63 
16.1.5 Signatures of Principal or Coordinating lnvestigator(S) and the key personnel 
involved in the conduct of the study ............................................................................ 63 
16. 1.6 Listing of subjects receiving test drug(s)/investigational product(s) from specific 
batches, where more than one batch was used ............................................................ 63 
16.1. 7 Randomization Schedule .................................................................................... 63 
16.1.8 Audit certificates ................................................................................................. 63 
16.1.9 Documentation of statistical methods ................................................................. 63 
16.1.1 0 Documentation of inter laboratory standardization methods and quality 
assurance procedures (lfUsed) .................................................................................... 63 
16.1.11 Publications based on the study ....................................................................... 63 
16.1.12 Important publications referenced in the report ............................................... 63 
16.2 SUBJECT DATA LISTINGS ...................................................................................... 63 
16.2.1 Discontinued subjects ......................................................................................... 63 
16.2.2 Protocol deviations ............................................................................................. 63 
16.2.3 Subjects excluded from the efficacy analysis ..................................................... 63 
16.2.4 Demographic data ............................................................................................... 63 
!6.2.5 Compliance and/or drug concentration data ....................................................... 63 
!6.2.61ndividual efficacy response data ....................................................................... 63 
16.2.7 Adverse event listings ......................................................................................... 63 
16.2.8 Listing of individual laboratory measurements by subject when required by 
regulatory authority ..................................................................................................... 63 
16.3 CASE REPORT FORMS ............................................................................................ 64 
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16.3. I CRFs for deaths, other serious adverse events and withdrawals for AE ............ 64 
16.3.20ther CRFs submitted ........................................................................................ 64 
I 6.4 INDIVIDUAL SUBJECT DATA LISTINGS ............................................................. 64 
16.5 BIOANALYTICAL REPORT .................................................................................... 64 
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List of Tables 
Table I: Summary of Plasma Pharmacokinetic parameters for digoxin- Treatment (A) ...... 1 0 
Table 2: Summary of Plasma Pharmacokinetic parameters for digoxin- Treatment (B) ....... I 0 
Table 3: Ratio and 90% Confidence Intervals of Treatment (A) versus Treatment (B) for 
digoxin ..................................................................................................................................... 11 
Table 4: Summary of Urine Pharmacokinetic parameters for digoxin- Treatment {A) ......... II 
Table 5: Summary of Urine Pharmacokinetic parameters for digoxin- Treatment (B) ......... 11 
Table 6: Identification of Investigational products .................................................................. 32 
Table 7: Investigational Product Accountability .................................................................... .33 
Table 8: Drug Administration ................................................................................................. .35 
Table 9: Subject disposition {All Subjects) ............................................................................ .42 
Table I 0: Summary Statistics for Untransformed Plasma PK Parameters of digoxin Per 
Treatment ................................................................................................................................. 46 
Table II Summary of Statistical Analysis of Ln-transformed Pharmacokinetic Parameters of 
digoxin .................................................................................................................................... .47 
Table 12 Summary Statistics for Untransformed Urine PK Parameters of digoxin Per 
Treatment ................................................................................................................................. 47 
Table 13: Summary Data of subjects enrolled and considered to establish DDI .................... 56 
Table 14: Plasma Pharmacokinetic Parameters of digoxin for Treatment A .......................... 57 
Table 15: Plasma Pharmacokinetic Parameters of digoxin for Treatment B ........................... 58 
Table 16: Urine Pharmacokinetic Parameters of digoxin for Treatment A ............................. 59 
Table 17: Urine Pharmacokinetic Parameters of digoxin for Treatment B ............................. 60 
Table 18: Abnormal Laboratory Value Listing ....................................................................... 61 
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List of Graphs 
Figure I Mean Plasma concentration vs time profiles - treatment wise of digoxin (Linear 
graph) .................................................................................................................................. .45 
Figure 2Mean Plasma concentration vs time profiles - treatment wise of digoxin (Semi-log 
graph) ................................................................................................................................. .45 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
% 
oc 
ADR 
AE 
ALT 
ANOVA 
AST 
AUCo-96 
BLQ 
BMI 
CDSCO 
CLR 
Crnax 
COA 
CP 
CRF 
CRO 
CSR 
DDI 
ESR 
fe 
HBsAg 
HCV 
HIV 
hr/hrs 
ICF 
ICH 
ICMR 
ICU 
ID 
IEC 
IP 
Percentage 
Degree centigrade 
Adverse Drug Reaction 
Adverse Event 
Alanine Amino Transferase 
Analysis of Variance 
Aspartate Amino Transferase 
Area under the plasma concentration versus time curve from time 
0 to the 96 hour time point concentration. 
Below Limit of Quantification 
Body Mass Index 
Central Drugs Standard Control Organization 
Renal Clearance 
Maximum measured plasma concentration 
Certificate of Analysis 
Clinical Pharmacology 
Case Report Form 
Contract Research Organization 
Clinical Study Report 
Drug-Drug Interaction 
Erythrocyte sedimentation rate 
Unchanged drug excreted in urine 
Hepatitis B Surface Antigen 
Hepatitis C Virus 
Human Immunodeficiency Virus 
Hours 
Informed Consent Form 
International Conference on Harmonization 
Indian Council of Medical Research 
Intensive Care Unit 
Identity Document 
Institutional Ethics Committee 
Investigational Product 
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IU 
K2EDTA 
kg 
LC-MS/MS 
Ln 
LOQ 
Ltd. 
M 
Meg 
mg 
mL 
MSE 
No. 
NR 
NS 
OTC 
P/A view 
PI 
PK 
RBC 
Rh 
rpm 
SAE 
SAS 
SD 
SGOT 
SGPT 
SOP 
Tmax 
VDRL 
WBC 
~hCG 
International Unit 
Di potassium Ethylene Diamine Tetraacetic Acid 
kilogram 
Liquid Chromatography tandem mass spectrometry 
Natural Logarithm 
Limit of Quantification 
Limited 
Missing samples 
Microgram 
Milligram 
Millilitre 
Mean Square Error 
Number 
Not reportable 
Non significant 
Over The Counter 
Posterior-Anterior view 
Principal Investigator 
Pharmacokinetic 
Red Blood Corpuscles 
Rhesus 
Rotations per minute 
Serious Adverse Event 
Statistical Analysis System 
Standard Deviation 
Serum Glutamic Oxaloacetic Transaminase 
Serum Glutamic Pyruvic Transaminase 
Standard Operating Procedure 
Time to achieve maximum plasma concentration 
Venereal Disease Research Laboratory 
White Blood Corpuscles 
Beta Human Chorionic Gonadotropin 
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5. 
ETHICS 
5.1 
INSTITUTIONAL ETHICS COMMITTEE (IEC) 
The final protocol No. C-CMP-SPI-001, Version No. 02 dated 07 Aug 2018 and other 
protocol related documents were reviewed and approved prior to study start by an 
Institutional Ethics Committee (IEC) as per below table. 
Document Name 
Document No. and Date 
Submission date Approval Date 
Protocol 
Version No. 02; dated 
07 Aug 2018 
Informed Consent 
Version No.: 02; dated 
Form (English) 
07 Aug 2018 
Informed Consent 
Version No.: 02; dated 
22 Aug 2018 
01 Oct 2018 
Form (Telugu) 
07 Aug2018 
Case Report Form 
Version No.: 02; dated 
13 Aug 2018 
Other supporting documents 
Amendment to the 
Amendment No.: 01; 
protocol 
dated 19Dec2018 
Informed Consent 
Version No.: 03; dated 
21 Dec2018 
22 Dec 2018 
Form (English) 
19 Dec 2018 
Informed Consent 
Version No.: 03; dated 
Form (Telugu) 
19 Dec 2018 
A list of the IEC members along with the IEC approval letter has been provided in 
Appendix 16.1.3. 
5.2 
ETHICAL CONDUCT OF THE STUDY 
This study was conducted in compliance with the final protocol No. C-CMP-SPI-001 
Version No. 02 dated 07 Aug 2018 and Amendment No 01 dated 19 Dec 2018, the 
applicable International Conference on Harmonization Guidelines for Good Clinical 
Practice (GCP), the relevant sections of Good Laboratory Practice (GLP), local laws 
and regulations (ICMR Guidelines on Biomedical Research, Schedule Y (amended 
version, 2014) of CDSCO (Central Drugs Standard Control Organization), relevant 
sections of Drugs and Cosmetics (First Amendment) Rules 2013, CDSCO 
Bioavailability & Bioequivalence guidelines, applicable USFDA guidelines, the 
provisions of Declaration of Helsinki (Brazil, October 2013) and applicable in- house 
SOP's. 
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5.3 
SUBJECT INFORMATION AND CONSENT 
Prior to screening of the volunteers, the screening consent form was provided as per 
the in-house SOP. Volunteers who were willing to participate in the screening process 
personally gave their consent by affixing their signature and date in the appropriate 
screening consent form. The volunteers were screened only after they voluntarily 
consented for the screening process. 
The study informed consent form was submitted with the protocol for review and 
approval by the ethics committee. The eligible volunteers were contacted by 
volunteer coordinating officer. They were given brief information about the study as 
per "study information sheet for the volunteer through Volunteer coordinating 
officer" and informed to visit the facility for further process. 
Further the volunteers interested in participating in the study were given a detailed 
explanation on the nature and extent of their participation in the study and the side 
effects that may occur in simple, non-technical language that suited the individual's 
level of understanding. All volunteers willing to participate in this study were 
provided a copy of the consent form describing this study and providing sufficient 
information for volunteers to make an informed decision regarding their participation 
in this study. Adequate opportunities were also provided for the volunteers to ask 
questions and contemplate participation. 
The formal consent of a volunteer, using the ethics committee approved consent form, 
was obtained before the volunteer underwent any study specific procedure. This 
consent form was signed and dated by the volunteer and by the investigator on 
10 Mar 2019. A copy of their signed informed consent document was provided to all 
subjects. 
A copy of' Study Information Sheet for the volunteer through Volunteer Coordinating 
Officer', English and Telugu JCFs are provided in Appendix 16.1.3. 
Space left blank intentionally. 
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' 
J 
Clinical Study Report J(lr Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Conlidential 
(L 
IN\'ESTICATORS AND STUDY AD~Hi\ISTRATI\'E STIH!CTlJHE 
The following are the key personnel involved in the conduct of the study 
-
~ 
Principal Investigator 
Dr. P. Venkatesh, MBBS 
Sub Investigator 
Dr. Sreedhar Reddy Peddi. MD General Medicine, 
DNB (cardiology) 
--
Clinical Investigator 
Dr. S. Ravikishore, MBBS 
f-----------·------------
-----~~-
--·----~--------~-------- ·--------- -
-·---~-------------
Study Coordinator 
Mr. T. Ani! Kumar, M. Pharm 
Bioanalytical Investigator Mr. Praveen Rao M. M. Sc 
PK Investigator 
Dr. Jagamnohan S. M. Phann, Ph.D .. PDF 
Statistical Investigator 
I Mr. Tushar Shinde, M. Sc 
Medical Writer 
I Mr. Ani! Kumar Mandadi, M. Pharm 
I Mr. Y.V.T.Rameswara Reddy, B. Phann 
In-charge - QA & RA 
Mr. Madhusudhan K. V, MSc. MBA 
A list of CV s of investigators involved in the clinical phase of the study and quality 
assurance are given in Appendix 16.1.4. 
Clinical Facility and 
ClinSync Clinical Research Pvt. Ltd., 
Screening Facility 
JSR Mall, Plot No.7 to 18, Madinaguda 
Village, Serilingampally Mandai, 
Hyderabad-500050, 
Telangana, India. 
Bioanalytical, 
ClinSync Clinical Research Pvt. Ltd., 
Pharmacokinetic and 
JSR Mall, Plot No.7 to 18. Madinaguda 
I Statistical Facility 
Village, Serilingampally Mandai, 
Hyderabad-500050, 
Telangana, India. 
Clinical Laboratory 
Medcis Pathlabs India Pvt. Ltd. 
I 
Plot 16 & I 7, Swathi plaza, 
I 
I 
. 
~ 
1 Bhavam Enclave. Anand Nagar, 
-
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Clinical Study Repot1 for Drug-Drug Interaction Study of Spironolactone and Digoxin 
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New Bowenpally, Secunderabad-500 0 I I. 
Phone: 07702 29 29 29 
Email: info@medcislabs.com 
X ray Facility 
ClinSync Clinical Research Pvt. Ltd. 
Clinical Pharmacology Department, 
JSR Mall, Plot No.7 to 18, Madinaguda Village, 
Serilingampally Mandai, Hyderabad-500050, 
Telangana, India. 
Institutional Ethics 
Vasavi Institutional ethics committee, 
Committee 
Vasavi Medical Research Center 
#6-l-91, Lakdikapul, Khairatabad, 
Hyderabad, Telangana 500004 
Phone no.: 040-65131333. 
Emergency Services 
Srikara Hospitals 
#222&223, Mythri Nagar, Phase-II, 
Madinaguda, Miyapur, Hyderabad-500049, 
Ph: 040-47470000, + 91772999 0002. 
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7. 
INTRODUCTION 
Patients frequently use more than one medication at a time. Unanticipated. 
unrecognized, or mismanaged DD!s are an important cause of morbidity and 
mortality associated with prescription drug use and have occasionally caused the 
withdrawal of approved drugs from the market. In some instances, understanding how 
to safely manage a DDI may allow the FDA to approve a drug that would otherwise 
have an unacceptable level of risk. 
The goal of a DDI study with pharmacokinetic endpoints is to inform clinical 
management strategies by determining whether there is a clinically significant 
increase or decrease in exposure to the substrate in the presence of the perpetrator. 
Clinical DDI studies compare substrate concentrations in the absence and presence of 
a perpetrator drug in vivo. 
The relevant concomitant medications for study include those used to treat the same 
condition for which the investigational drug is being studied or those used to treat 
common co-morbidities in the patient population. 
The purpose of most DDI studies is to determine the ratio of a measure of substrate 
drug exposure (e.g., AUC ratio) in the presence and absence of a perpetrator drug. 
Spironolactone is a specific pharmacologic antagonist of aldosterone indicated for 
primary hyperaldosteronism, Severe heart failure, Edematous conditions for patients 
with congestive heart failure, Cirrhosis of the liver, Essential Hypertension, 
Hypokalemia, and Nephrotic syndrome. 
Digoxin is the cardiac (or digitalis) glycoside, having effects on the myocardium and 
is indicated for the treatment of mild to moderate heart failure, and atrial fibrillation. 
Spironolactone and its metabolites interfere with radio immunoassays for digoxin and 
increase the apparent exposure to digoxin. It is unknown to what extent, if any, 
spironolactone may increase actual digoxin exposure. In patients taking concomitant 
digoxin, use an assay that does not interact with spironolactone. 
This study was conducted in healthy subjects. The design of this study addresses the 
primary objective to characterize the pharmacokinetic profile of Digoxin (substrate 
drug) in the presence and absence of spironolactone (perpetrator) in healthy adult 
human subjects under fasting condition. 
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8. 
STUDY OBJECTIVES 
• 
Primary objective 
To characterize the pharmacokinetic profiles of Digoxin (substrate drug) in the 
presence and absence of spironolactone (perpetrator) in healthy adult human 
subjects under fasting condition. 
• 
Secondary objective 
To assess whether there is a drug-drug interaction with concomitant use of 
spironolactone. 
To measure renal clearance (CLR)/Percent Recovered and unchanged drug 
excreted in urine ( fe )I Amount Recovered for digoxin in the presence and absence 
of spironolactone (perpetrator) in healthy adult human subjects under fasting 
condition. 
To monitor safety of the subjects in drug-drug interaction study. 
Space left blank intentionally. 
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9. 
INVESTIGATIONAL PLAN 
9.1 
OVERALL STUDY DESIGN AND PLAN- DESCRIPTION 
Study Design 
This study was designed as an open label, balanced, randomized, single-dose, 
two-treatment, two-sequence, two-period, crossover, drug-drug interaction study in 
healthy adult human subjects under fasting condition. 
Number of Subjects 
28 healthy adult male human subjects were enrolled in the study. 
Washout period 
Washout between treatments: 28 days. 
Method of Blinding 
This was a randomized open label study. The study personnel involved in the sample 
analysis were kept blinded from the randomization code during entire study. 
Method of Assignment to treatment 
The subjects were randomly assigned to one of the possible sequences of treatment A 
and treatment B as per the randomization scheme generated at ClinSync Clinical 
Research Pvt. Ltd. according to SAS® (version 9.3). 
Either the treatment A or treatment B were administered to 28 subjects in each period 
of the study. 
In both periods (Period-! and II), from Day I to Day 5 and Day 7 to Day 9, the 
subjects who were randomized to treatment B, were administered Spironolactone 
Oral Suspension I 00 mg (Perpetrator; Carospir® Oral Suspension 20 mL of 25 mg I 5 
mL), and the subject who were randomized to treatment A were not dosed. On all 
these days the standard breakfast was served 0.50 hr (30 min) post dose. On Day 6, 
after overnight fasting of at least I 0.00 hours the subjects were dosed either with the 
treatment A [LANOXIN® (digoxin) USP 250 meg (substrate drug)] or treatment B 
[LANOXIN® (digoxin) USP 250 meg (substrate drug) + Spironolactone Oral 
Suspension I 00 mg (Perpetrator; Carospir® Oral Suspension 20 mL of 25 mg I 5 mL] 
as per the randomization scheme. 
Sequence and Duration of Study Periods 
This study was a two treatment, two period, two sequence design. A single oral dose 
of treatment A and treatment B was administered in period I and period II separated 
by a wash out period of 28 days between the dosing. The duration of the study from 
the check in of period I to the last blood sample collection in period II was 39 days. 
Housing 
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Subjects were checked-in to the clinical facility 11.00 hours prior to the drug 
administration on Day I and remain housed in the clinical facility until the collection 
of 96.00 hours blood sample on Day I 0 in each of the study periods. On day 6 the 
subjects were fasted for at least I 0.00 hours prior to dosing. 
The protocol and sample case report form have been attached as Appendix 16.1.1 and 
Appendix 16.1.2, respectively. 
9.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS 
This study was designed as an open label, balanced, randomized, single-dose, 
two-treatment, two-sequence, two-period, crossover, drug-drug interaction study. 
The washout period has been chosen based on the elimination half-life of digoxin, 
such that at least 5-7 half-lives have elapsed after drug administration. The blood 
collection time points were chosen to accurately characterize the absorption and 
elimination phases of the plasma concentration versus time curve obtained after 
dosing. 
9.3 
SELECTION OF STUDY POPULATION 
A total of28 healthy adult male human subjects who met all the inclusion and none of 
the exclusion criteria, were enrolled in the study. 
Selection of subjects was done as per the following inclusion and exclusion criteria. 
9.3.1 
Inclusion Criteria 
Volunteer who participated in the study: 
a. Healthy human subjects aged between 20 and 35 years (including both) 
b. Subjects with a BMI between 18.5 - 24.9 Kg/m2 (including both) but body weight 
not less than 60 Kgs. 
c. Subjects who were screened at least 48 hours prior to check-in. 
d. Subjects with normal health as determined by personal medical history, clinical 
examination, and laboratory examinations including serological tests during the 
screening. 
e. Subjects with normal 2D echo. 
f. 
Subjects with normal 12-lead electrocardiogram (ECG) or ECG with no clinical 
significant abnormalities as determined by Investigator. 
g. Subjects with normal chest X-Ray (PIA view) or chest X-ray with no clinically 
significant abnormalities as determined by investigator. 
h. Subjects able to communicate effectively. 
1. 
Subjects willing to give written informed consent and adhere to all the 
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requirements of this protocol. 
9.3.2 
Exclusion Criteria 
Any of the following conditions were cause for exclusion from the study: 
Confidential 
a. Subjects having contraindications or hypersensitivity to study drug or related 
group of drugs. 
b. History or presence of any medical condition or disease according to the opinion 
of the physician. 
c. History or presence of significant cardiovascular, pulmonary, hepatic, renal, 
gastrointestinal, endocrine, immunological, dermatological, neurological or 
psychiatric disease or disorder. 
d. Subject having QT/QTc interval >450 milliseconds. 
e. History or presence of significant alcoholism or drug abuse in the past one year. 
f. History or presence of significant smoking (more than l 0 cigarettes or beedies 
/day or consumption of tobacco products). 
g. Subjects who failed to abstain from consuming any alcoholic products from 48.00 
hours prior to check-in to till check-out I last sample of the study. 
h. Subjects who failed to abstain from any xanthine-containing food and/or 
beverages (like chocolate, tea, coffee, cola drinks), cigarettes and tobacco 
containing products and grapefruit and/or it's juice from 48.00 hours prior to 
check-in to till check-out I last sample of the study. 
i. 
Subjects who failed to refrain from pan or pan masala, gutkha, masala (containing 
beetle nut and tobacco) for 48.00 hours prior to check-in to till check-out/last 
sample of the study. 
J. 
Difficulty with donating blood. 
k. Systolic blood pressure less than 110 mm Hg or more than 140 mm Hg. 
I. Diastolic blood pressure less than 70 mm Hg or more than 90 mm Hg. 
m. Pulse rate less than 60 beats/minute or more than I 00 beats/minute. 
n. Use of any prescribed medication during last two weeks or OTC medicinal 
products/ herbal products during the last one week prior to check-in. 
o. Major illness during 90 days before check-in. 
p. Participation in a drug research study within past 90 days of check-in. 
q. Donation of blood (i.e. one unit or 350 mL) in the past 90 days before check-in. 
r. 
Unusual diet consumption in the past 3 weeks before check-in. 
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9.3.3 
Removal of Subjects from Study or Assessment 
• 
If the subject was non-cooperative and non-compliant. 
• 
If the subject found to have entered the study in violation of this protocol. 
• 
If any subject experienced emesis at or before 2 times median T ma> on Day 6. 
• 
The subject who are suffering from any other clinically significant adverse event. 
• 
The subject who received/required any concomitant medication, which may 
interfere with the pharmacokinetic property of the study drug. 
• 
The subject who underwent/required hospitalization during the course of the 
study. 
• 
The subject who reported to the clinical facility for check-in after the prescribed 
time limit there by failing to meet the protocol requirements. 
• 
If it was felt in the investigator's opinion that it is not in the subject's best interest 
to continue. 
• 
The subject who was tested positive for Alcohol breath test. 
• 
The subject who was tested positive for any one of the urine drugs of abuse. 
• 
Subjects who missed 03 consecutive blood draws in a study period. 
All the subjects were advised that they were free to withdraw from the study at any 
time. They were also informed that they could be withdrawn from the study by the 
Principal Investigator/clinical investigator and/ or sponsor in case of un-necessary 
risk, adverse events or non-compliance. 
9.4 
TREATMENTS 
9.4.1 
Treatments Administered 
From 11 Mar 2019 (Day 1) to 15 Mar 2019 (Day 5) and from 17 Mar 2019 (Day 7) to 
19 Mar 2019 (Day 9) in period I; from 08 Apr 2019 (Day 1) to 12 Apr 2019 (Day 5) 
and from 14 Apr 2019 (Day 7) to 16 Apr 2019 (Day 9) in period II, the subjects who 
were randomized to treatment B were administered Spironolactone oral Suspension 
100 mg (Perpetrator; Carospir® Oral Suspension 20 mL of 25 mg I 5 mL) and in both 
period I and II, subjects who were randomized to treatment A were not dosed. 
On day 6, after a supervised overnight fasting of 10.00 hours, the subjects were 
administered a single oral dose of either the Treatment A LANOXIN® (digoxin) USP 
250 meg (substrate drug) or Treatment B LANOXIN® (digoxin) USP 250 me@ 
(substrate drug) + Spironolactone Oral Suspension I 00 mg (Perpetrator; Carospir 
Oral Suspension 20 mL of 25 mg I 5 mL) on 16 Mar 2019 in period I and on 
13 Apr 2019 in period II, as per the randomization scheme, under fasting condition. 
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The drug administration details are tabulated in section 9.4.5. 
9.4.2 
Identity of Investigational Products 
Receipt and storage 
The Investigational Products along with the Certificates of Analysis (COA) sent by 
the sponsor were received by the pharmacist. The receipt of the Investigational 
Products was recorded in the appropriate log. The pharmacist verified that the 
shipment contains all the items noted in the shipment inventory and also with respect 
to the COA of the Investigational Products in presence of Quality assurance 
personnel. 
The Investigational Products were stored in locked cabinets in the access controlled 
pharmacy, which is a secure area, at storage conditions as mentioned in the product 
label and as per in house SOPs. Access to Investigational Products was provided only 
to the pharmacist. The Investigational Products were dispensed as per the 
randomization scheme by the pharmacist in presence of Quality assurance personnel. 
The details of the study products are provided in the table below. 
Table 6: Identification of Investigational products 
Dosage form 
Tablet 
Suspension 
Drug Name 
LANOXIN® (digoxin) USP 250 meg 
Carospirv Oral Suspension 20 mL of 25mg I 
5 mL (Spironolactone I 00 mg) 
Manufacturer 
--
CMP Development LLC, USA 
Concordia Phannaceuticals Inc., St. 
Manufactured for 
Michael, Barbados BBII005. Initial 
--
u.s 
Lot Number 
AH3690B 
1118211 
Manufacturing Dat 
18/08/2017 
21/11/2018 
Expiry Date 
07/2021 
11/2020 
* As per study drug receipt checklist and acknowledgement form 
Records of the receipt and dispensing of study products were made to provide 
complete accountability of the disposition of all supplies. The investigational product 
accountability details are summarized in table below. 
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Table 7: Investigational Product Accountability 
--
---
Quantity 
Quantity 
Carospir® Oral 
Particulars 
Period 
Suspension 20 mL 
of25mg/5 mL 
Date 
LANOXIN® 
Date 
(digoxin) USP 
(Spironolactone 
250 meg 
100 mg) 
06 bottles 
29 Jan 2019 
(2838 mL) 
Received 
19 bottles 
300 tablets* 
29 Jan 2019 
(8987 mL) 
02 Mar 2019 
Period 
280 ml x 09 days + 
II Mar 2019 
to 19 Mar 
28+01' 
15 Mar 2019 
I 
20 ml x 09 days' 
2019 
Dispensed 
08 Apr 2019 
Period 
280 ml x 09 days + 
to 16 Apr 
28 + 01 # 
12 Apr2019 
II 
# 
20 ml x 09 days 
2019 
Period 
11 Mar 2019 
I 
280 m1 x 09 days 
to 19 Mar 
28 
16Mar2019 
Dosed 
2019 
Period 
08 Apr 2019 
II 
280 ml x 09 days 
to 16Apr 
28 
13 Apr2019 
2019 
Remaining Quantity 
14 bottles 
244 
(6425 mL) 
--
--
Sent to client 
Nil 
NA 
Nil 
NA 
'- 20 mL ofCarospir® oral suspension extra dispensed form Day 01 to Day 09 in each period; '01 
tablet of LANOXIN® (digoxin) extra dispensed on day 6 in each period. 
*- 01 tablet ofLANOXIN® (digoxin) were used for physical verification. 
Note: 20 mL of Carospir® oral suspension extra dispensed form Day 01 to Day 09 in each period was 
discarded after dosing under running tap water. 
Storage: 
The test and the reference products were stored in the pharmacy at appropriate 
storage conditions. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
In order to avoid bias, the statistician generated a randomization scheme using 
statistical analysis software SAS® (Version 9.3). Subjects were randomly assigned to 
one of the two sequences based on this randomization scheme and was kept under 
controlled access. 
The details of the subjects with the treatments assigned are provided in 
Appendix 16.1.7. 
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9.4.4 
Selection of Doses in the Study 
The Treatment A consisted of a single oral dose of LANOXJN@ (digoxin) USP 
250 meg (substrate drug) and the Treatment B consisted of a single oral dose of 
LANOXIN® (digoxin) USP 250 meg (substrate drug) + Spironolactone Oral 
Suspension 100 mg (Perpetrator; Carospir® Oral Suspension 20 mL of25 mg I 5 mL). 
The drug-drug interaction (DDI) study using 250 meg dose with 28 subjects would be 
useful to establish DDI of digoxin. 
9.4.5 
Selection and Timing of Dose for each Subject 
In each period, from Day I to Day 5 and Day 7 to Day 9, the subjects who were 
randomized B, were administered Spironolactone Oral Suspension I 00 mg 
(Perpetrator; Carospir® Oral Suspension 20 mL of 25 mg I 5 mL) and who were 
randomized A were not dosed. On these days standard breakfast was served 0.50 hr 
(30 min) post dose. 
On Day 6, the subjects underwent supervised overnight fasting for I 0.00 hours before 
drug administration. Treatment A or Treatment B was administered orally to the 
subjects according to randomization scheme on Day 6. In case of subjects who were 
assigned Treatment A, single oral dose of LANOXIN® (digoxin) USP 250 meg was 
administered with 240 ± 2 mL of water under fasting condition. Subjects swallowed 
the tablet as a whole. Dosing compliance was assessed by oral cavity check. 
In case of subjects who were assigned Treatment B, single oral dose of LANOXIN® 
(digoxin) USP 250 meg was administered with 120 mL of water under fasting 
condition and Carospir® (spironolactone) Oral Suspension 100 mg (20 mL of25 mg I 
5 mL) was administered with 120 mL of water with a graduated syringe. 
CaroSpir (spironolactone) oral suspension administration procedure 
20 mL of25 mg I 5 mL ofCarospir® (spironolactone) oral suspension was loaded in 
the syringes well in advance prior to dosing on the day of dosing. The suspension in 
the syringe was directly administered to the subjects. Then the syringe was rinsed 
with approximately 10 mL from 120 mL of dosing water and administered to the 
subjects. This rinsing procedure was done until the syringe was free of the contents of 
the medication. Then the remaining quantity of water from the assigned 120 ml water 
was finally administered to the subjects. 
A washout period of 28 days separated the two periods. 
On Day 6, subjects who are dosed remained in a supine position or semi recumbent 
position for 03 hours post-dose and only necessary movement was allowed during 
this period. Thereafter subject was allowed to ambulate freely during the remaining 
part of the study. Subject did not sit down (except as directed by the physician 
secondary to adverse events) during restriction period. 
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In each period on each day from Day 
to Day 5 and from Day 7 to Day 9, the 
subjects were served the standard breakfast, Lunch, Snacks and dinner at 0.50, 4.00, 
8.00, and I2.00 hours post dose. On day 6, lunch, snacks and dinner were served at 
4.00, 8.00, and 12.00 hours post dose. Meal plans were identical for both the study 
periods. On Day 6, water was provided ad libitum during the study, except I hour 
before and I hour after dosing except during drug administration. 
Drug administration details are provided in the table below. 
Table 8: Drug Administration 
Period Number 
Subject Number 
Drug Administration 
Treatment A 
Treatment B 
Date 
Time 
--
01, 15 
08:30 
02, 16 
--
08:32 
17 
03 
08:34 
04 
18 
08:36 
19 
05 
08:38 
06 
20 
08:40 
21 
07 
08:42 
One 
08 
22 
08:44 
--
09,23 
II Mar2019to 
08:46 
19 Mar 2019 
10,24 
--
08:48 
25 
II 
08:50 
12 
26 
08:52 
13 
27 
08:54 
28 
14 
08:56 
01, 15 
--
08:30 
--
02, 16 
08:32 
03 
17 
08:34 
18 
04 
08:36 
05 
19 
08:38 
20 
06 
08:40 
07 
21 
08 Apr 2019 to 
08:42 
Two 
22 
08 
16 Apr2019 
08:44 
09,23 
--
08:46 
--
10,24 
08:48 
II 
25 
08:50 
26 
12 
08:52 
27 
13 
08:54 
14 
28 
08:56 
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Treatment A: LANOXIN (digoxin) USP 250 meg 
Treatment B: LANOXIN® (digoxin) USP 250 meg+ Carospir@(spironolactone) oral suspension 100 mg 
(20 mL of25 mg 15 mL) 
9.4.6 
Blinding 
This study was designed as an open label study. However, the bioanalytical scientists 
who perfonned the analysis were blinded to the treatment during subject sample 
analysis to avoid bias. 
9.4. 7 Prior and Concomitant Therapy 
No concomitant medication was administered since there were no AEs recorded in 
the study. 
9.4.8 
Treatment Compliance 
In each period, from Day I to Day 5 and Day 7 to Day 9, the subjects who were 
assigned B, received LANOXIN® (digoxin) USP 250 meg + Spironolactone Oral 
Suspension 100 mg (Carospir® Oral Suspension 20 mL of25 mg I 5 mL) and subjects 
who were assigned A were not dosed. All the subjects swallowed the drug as a whole. 
On Day 6, subjects received a single dose of the Treatment A or Treatment B in each 
period. All the subjects swallowed the drug as a whole. 
The Principal investigator or qualified designate, was responsible for ensuring that the 
administration of timed oral doses was conducted. Additionally, to ensure subject 
compliance, study personnel conducted oral cavity check immediately after drug 
administration. 
9.5 
EFFICACY AND SAFETY VARIABLES 
9.5.1 
Pharmacokinetic and Safety Measurements Assessed 
Pharmacokinetic measurements assessed: 
The following pharmacokinetic parameters for digoxin were obtained using 
non-compartmental method (WinNonlin, version 8.1, Pharsight Corporation, USA): 
Cmax, AUCo.96 and tmax 
Safety Assessment: 
Subjects were monitored for safety during the study and until the completion of the 
study. Safety assessments were done based on clinical observations, laboratory data at 
the beginning and at the end of the study and evaluation of the AEs observed during 
the course of the study. 
Screening assessment comprised of detailed demographic data and medical history 
followed by general physical examination and systemic examination and laboratory 
investigations (hematology, biochemistry, urine analysis and serology), vitals, ECG 
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(done within 28 days prior to check in of period one), 2D echo and chest X-ray (done 
within 6 months prior to check in of period one). 
Subjects were monitored for safety during the entire study. The subject's Clinical 
examination along with vital signs (seated blood pressure, radial pulse rate and 
oral/aural temperature) were measured during check-in and check-out of each period. 
Clinical examination was done on prior to dosing on Day 06 in each study period. 
Oral/aural temperature was measured prior to dosing in each study period. 
Vital parameters- seated blood pressure and radial pulse rate were measured at prior 
to dosing, 1.00, 3.00, 5.00 and 11.00 hours post dose in each period from Day I to 
Day 5, and from Day 6 to Day 9, vitals were measured prior to dosing, at 1.00, 2.00, 
3.00, 5.00, 8.00 and 11.00 hours post dose in each period. 
Note 
• 
On Day 6 the Vital signs (i.e. up to 3.00 hours post dose) was performed at 
bed side. 
• 
For subjects who were randomized to treatment A, the vitals were checked at 
5.00 hours post dose during day I to Day 5. 
ECG was performed at 1.00 and 3.00 hours post dose in each period on Day 6, before 
period II check-in for subject study eligibility and at check-out of each period of the 
study. 
In each study period creatinine clearance and serum potassium levels were measured 
on Day 05 for the dosing eligibility of the subjects. 
For the safety of the subjects, hematology (except blood grouping and Rh typing) and 
biochemistry (except random blood sugar) investigations were repeated at the end of 
the study. 
9.5.2 Appropriateness of Measurements 
The blood sampling points were chosen such that T max could be accurately 
characterized for digoxin. In addition, sampling was done up to 96.00 hours post dose 
such that the plasma concentration could be measured for adequately profiling the 
pharmacokinetics of the product. 
All safety assessments chosen were standard and widely used and are documented in 
the appropriate section of the case report forms (CRFs). 
9.5.3 
Primary Pharmacokinetic Variable(s) 
The primary pharmacokinetic variables calculated in the study were Cmax and AUC0.96 
for digoxin. The absence of drug-drug interaction was based on the 90% Confidence 
Intervals (CI) of the above parameters. 
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9.5.4 
Drug Concentration Measurements 
9.5.4.1 Blood Sampling 
Confidential 
On Day 6, a total of 25 (I x 5 mL) blood samples were collected for each subject in 
pre-specified vacutainer tubes containing anticoagulant (K2EDTA) in each study 
period. The pre-dose sample was collected within 2 hours prior to drug 
administration. The post-dose blood samples were collected at 0.25, 0.50, 0. 75, 1.00, 
1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.SO, 4.00, S.OO, 6.00, 8.00, I 0.00, 12.00, 16.00, 
24.00, 36.00, 48.00, 60.00, 72.00 and 96.00 hours in each study period. 
Note: Blood samples up to 3 hours post dose were collected at bed side. 
The pre-dose and post-dose samples up to 24.00 hours were collected via an 
indwelling cannula placed in an ante-cubital vein or one of the forearm veins inserted 
prior to first sample collection in each period and 36.00, 48.00, 60.00, 72.00 and 
96.00 post dose samples were collected by a fresh vein-puncture. 
All the blood draws up to 96.00 hours were done in-house. The collected blood was 
transferred immediately after collection in vacutainer tubes containing anticoagulant 
(K2EDTA) in each of the two study periods. 
Sample Processing: 
The vacutainers containing blood samples obtained from the subjects were 
centrifuged in a refrigerated centrifuge at 4000 rpm for I 0 minutes at 4 °C. The 
separated plasma was transferred to pre-labeled polypropylene tubes to make equal 
aliquots, for all the samples. 
Blood volume: 
The total volume of blood collected during the entire study did not exceed 292 mL for 
each subject. However, additional blood (3-S mL) would be collected for repeat/ 
additional 
investigations when 
significant abnormalities 
in 
the 
laboratory 
investigations were observed. 
Sample Storage and Shipping: 
All plasma samples were stored in a freezer at a temperature of -20 ± soc up to 
4.00 hours and then were transferred to -70 ± IS°C at the clinical site. Prior to 
shipping, the samples were packed into thermal insulated containers and packed in 
sufficient dry ice to assure that they remained frozen and were protected from 
breakage during shipment. The plasma samples were transferred from cold chain 
management (CCM) department to bioanalytical facility on 23 Apr 2019 for analysis 
batch wise as per approved sequence schedule, after the completion of clinical phase. 
9.5.4.2 Urine Sampling 
On Day 6, a total of II urine samples were collected from each subject in each study 
period at intervals of (0.00-1.00), ( 1.00-2.00), (2.00-4.00), ( 4.00-6.00), (6.00-8.00), 
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(8.00-12.00), ( 12.00-16.00), ( 16.00-24.00), (24.00-48.00), ( 48.00-72.00) and (72.00-
96.00) hours post dose. 
Immediately out of the total volume of urine collected at each collection time interval, 
approximately I 0 mL (2 x 5 mL aliquots) of urine samples were transferred into two 
pre-labeled containers for analysis. They were stored at deep freezer maintained 
at-20°C or lower until dispatched from Clinical Unit to Bioanalytical Department on 
24 May 2019 for analysis. The analysis was done after the completion of clinical 
phase. 
The urine samples were stored at -20°C or lower in the Bioanalytical facility until 
analysis. After collecting the urine samples from all the subjects at each collection 
time interval, the total pooled volume was recorded. 
9.5.4.3 Method of Measurement 
The plasma and urine samples were shipped to the bioanalytical facility of ClinSync 
Clinical Research Pvt Ltd, Hyderabad, India, where the samples were analyzed to 
determine the drug concentrations. The drug concentrations were determined from all 
the plasma samples received from the clinical phase using a validated LC-MS/MS 
method. 
9.6 
DATA QUALITY ASSURANCE 
A systematic and independent examination of study activities and documents was 
conducted to determine whether the activities were conducted, and the data were 
recorded, analyzed, and accurately reported according to the protocol, Standard 
Operating Procedures (SOPs), Good Clinical Practice (GCP), Good Laboratory 
Practice (GLP) and other applicable regulatory requirement(s). 
The quality assurance unit audited every phase of the study from enrollment of 
subjects into the study to the accurate and completeness of the final reports. The QA 
statement/declaration is given in Appendix 16.1.8. 
9.7 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE 
9. 7.1 
Statistical and Analytical Plans 
9. 7.1.1 Pharmacokinetic Analysis 
Pharmacokinetic parameters for 
digoxin was calculated from the plasma 
concentration data and urine data were obtained from all the subjects who completed 
both the periods, using standard, non-compartmental methods with WinNonlin® 
Software (version 8.1, Pharsight Corporation, USA). The definition and method of 
determination for each pharmacokinetic variable is summarized as follows: 
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Primary Pharmacokinetic parameters in plasma 
Cmax 
AUCo-96 
Maximum measured plasma concentration. 
Area under the plasma concentration versus 
time curve from time 0 to the 96 hour time point 
concentration. 
Secondary Pharmacokinetic parameters 
Tmax 
Time to achieve maximum plasma 
concentration. If the maximum value occurs at 
more than one time point, T max is defined as the 
first time point with this value. 
Pharmacokinetic parameters in urine 
CLR 
fe 
Renal clearance Aeo-24oh!AUCo--24o h 
Unchanged drug excreted in urine 
Concentration-time data that were below limit of quantification were treated as zero 
for calculations and summary statistics. 
Pharmacokinetic analyses included data from samples of subjects who completed 
both periods of the study. 
Descriptive statistics for concentration data were presented for scheduled (nominal) 
sampling times. Actual elapsed times were used for all pharmacokinetic and statistical 
analyses only if the samples were withdrawn outside of the permitted window period. 
Samples lost I not received from the clinical site, samples processing or arising due to 
drop out or withdrawal of subjects were to be denoted by the character "M" and 
excluded from pharmacokinetic analysis. 
9. 7.1.2 Statistical Analysis 
Statistical analysis was performed using the SAS® software version 9.3 (SAS Institute 
Inc., Cary NC, USA) for digoxin. The following summary statistics for the 
pharmacokinetic parameters were calculated for both the Treatment A and 
Treatment B: Number of Subjects (N), Arithmetic Mean (Mean), Standard Deviation 
(SD), Minimum, Maximum, Median and Percentage Coefficient of Variation (CV%). 
Additionally, Geometric Mean (GM) was estimated for Cmax and AUCo.96· 
The log transformed pharmacokinetic parameters (Cmax and AUC0.96 for digoxin) 
were analyzed using Type Ill sum of squares, with the main effects of formulation, 
period, sequence and subjects nested within sequence as random effect. The 90% 
confidence intervals for the difference between drug formulation least-square means 
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(LSM) were calculated for the parameters Cm"' and AUC0.96 using log transformed 
data. 
9.7.2 
Determination of Sample Size 
A total of 28 healthy human adult subjects were included in the study. Additionally, 
04 stand-by subjects were included in order to dose 28 subjects in period I. As the 
same perpetrator (LANOXIN® Tablets USP 250 meg) would be given to both the 
treatments and only the difference could be with and without spironolactone oral 
suspension, 28 subjects along with 04 stand-by subjects would be sufficient to 
provide a reliable estimate of the magnitude and variability of the interaction. 
9.8 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
There were no changes in the clinical conduct of the study or planned analyses. The 
study was conducted as per the IEC approved Protocol. 
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10. 
STUDY SUBJECTS 
10.1 
DISPOSITION OF SUBJECTS 
A total of28 + 04 (standby subjects) healthy adult human male subjects were enrolled 
in the study. All these 28 subjects were dosed in Period-! and Period-11 of the study. 
The following table summarizes the subject disposition: 
Table 9: Subject disposition (All Subjects) 
Sequence I 
Sequence 2 
All 
AB 
BA 
Subjects 
Subjects 
Randomized 
14 
14 
28 
Completed 
14 
14 
28 
Discontinued 
00 
00 
00 
Treatment A: LANOXIN® (digoxin) USP 250 meg (substrate drug) 
Treatment B: LANOXIN® (digoxin) USP 250 meg + Spironolactone Oral Suspension I 00 mg 
(Carospir® Oral Suspension 20 mL of25 mg 15 mL) 
10.2 
PROTOCOL DEVIATIONS 
Protocol Deviations occurred during the entire duration of the study was presented in 
the Appendix 16.2.2. 
Sample Centrifuge Deviation 
The 0.25 hr sample in period I was centrifuged 45 minutes beyond the scheduled time 
of blood sample collection 
Blood Sample Collection Deviations 
There were three sample collection deviations reported in this study. 
11.00 hours post dose vitals Deviations 
There were seven post dose vitals deviations were recorded in this study. 
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11. 
PHARMACOKINETIC EVALUATION 
11.1 
DATASETSANALYSED 
A total of 28 subjects were dosed and randomized. All these 28 subjects had 
evaluable pharmacokinetic parameters for both the periods I and 2 and were included 
in Pharmacokinetic analysis. 
Pharmacokinetic analysis was performed on plasma concentration data and urine 
concentration data from subject nos. 0 I - 28. 
11.2 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
A total of 28 subjects were enrolled in this study. All subjects were healthy human 
adult male subjects of South Asian race (Indian). Their mean (±SD) age was 28.86 ± 
3.51 years (range 20 to 35), mean (±SD) height, weight and BMI were 169.21 ± 5.79 
ems (range 156 to 180), 66.50 ± 4.11 kg (range 60.50 to 74.20) and 23.27 ± 1.68 
kg/m2 (range 19.61 to 24.86) respectively. 
A table detailing the subject wise demographic characteristics is given in 
Appendix 16.2.4. 
11.3 
MEASUREMENTS OF TREATMENTS COMPLIANCE 
Treatment compliance was measured by analysis of plasma and urine samples to 
determine the concentration of digoxin following the administration of Treatment A 
and Treatment B. 
The assessment of treatment compliance was performed as given under section 9.4.8. 
The analysis of the clinical samples was performed as explained under section 9.5.4. 
The details of the validated methods are provided in separate method validation report 
given in Appendix 16.5. 
The samples were analyzed using the above validated method. 
The quality control samples were prepared and distributed between subject samples in 
each analytical run both in the presence and absence of spiranolactone and its 
metabolite canrenone. 
Quality Control samples were analyzed with samples in order to monitor the accuracy 
and precision of the validated method to ensure that the method continues to perform 
satisfactorily. The details of the subject analysis are provided in a separate 
bioanalytical report given in Appendix 16.5. 
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11.4 
PHARMACOKINETIC RESULTS AND TABULATIONS OF INDIVIDUAL 
SUBJECT DATA 
I 1.4.1 Pharmacokinetic & Statistical Analysis 
Pharmacokinetic analysis of the plasma and urine concentrations for digoxin was 
carried out for Treatment A and Treatment B to determine the following PK 
parameters in each individual subject using Phoenix WinNonlin version 8.1. The 
results are given below: 
Concentration-time data that are below limit of quantification were treated as zero for 
calculations and summary statistics. 
Summary statistics for concentration data were presented for scheduled (nominal) 
sampling times while actual elapsed times were used for all pharmacokinetic and 
statistical analyses unless the samples were withdrawn within the permitted window 
period. 
The mean concentration-time profiles of digoxin in plasma after administration of 
Treatment A and Treatment B are presented in Figure I and Figure 2 respectively. 
Summary statistics ofPK parameters per treatment for digoxin are shown in Table 10. 
Summary statistics of pharrnacokinetic profile of digoxin (substrate drug) in the 
presence and absence of spironolactone (perpetrator) was provided based on plasma 
and urine data. Renal clearance (CLR)/Percent Recovered and unchanged drug 
excreted in urine (fe)/ Amount Recovered for digoxin was measured and provided as 
a supporting data (evidence) in Table 12. 
All the subjects included in the pharrnacokinetic analysis had sufficient quantifiable 
concentrations versus time and no exclusions were considered with respect to 
pharrnacokinetic analysis. 
Protocol No. C-CMP-SPI-001 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
Figure 1 Mean Plasma concentration vs time profiles- treatment wise of digoxin 
(Linear graph) 
~ :woo-
g 
-~ 
" 
1500-
§ 
u 
~ >000-
El 
i'.l 
0: ' £ >OO- \.. 
0 
0.00 
20.00 
40.00 
60.00 
80.00 
100.00 
Time {Hr) 
Figure 2 
Mean Plasma concentration vs time profiles -treatment wise of digoxin 
(Semi-log graph) 
!0000-
!
Treatment -6- ':est-~ j 
--B-1~ 
!0~----------~,---------r----------r-,---------r----------~ 
0.00 
20.00 
40_00 
60.00 
80.00 
100.00 
Time (Hr) 
Protocol No. C-CMP-SPI-001 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
Table 10: Summary Statistics for Untransformed Plasma PK Parameters of digoxin Per 
Treatment 
Treatment 
Statistics 
Cmax 
AliCo-96 
Tmax 
(ng/mL) 
(ng.hr/mL) 
(h) 
N 
28 
28 
28 
Mean 
1530.188 
13715.974 
0.744 
SD 
502.810 
2669.003 
0.195 
-< -
Min 
644.613 
8632.172 
0.500 
t: 
"' 
E 
Median 
1429.822 
13440.345 
0.750 
-
ro 
~ 
Max 
2734.608 
21455.761 
1.330 
Geometric Mean 
1456.085 
13473.043 
0.721 
CV % Geometric 
32.993 
19.431 
25.996 
Mean 
Treatment 
Statistics 
Cmax 
AUCa-,. 
Tmn 
(ng/mL) 
(ng.hr/mL) 
(h) 
ill -
c 
"' 
E 
til 
0) 
.... 
f-. 
N 
28 
28 
28 
Mean 
2432.908 
16551.500 
0.901 
SD 
870.562 
4108.500 
0.569 
Min 
539.707 
6373.657 
0.500 
Median 
2422.385 
17151.091 
0.750 
Max 
5044.130 
23997.624 
3.500 
G. Mean 
2254.118 
15996.644 
0.810 
G.mean%CV 
45.789 
28.453 
44.310 
Treatment A: LANOXIN® (digoxin) USP 250 meg (substrate drug) 
Treatment B: LANOXIN® (digoxin) USP 250 meg + Spironolactone Oral Suspension I 00 mg 
(Carospir® Oral Suspension 20 mL of25 mg I 5 mL) 
The median time to reach peak plasma concentration (T max) for digoxin was 0. 750 hr 
and 0.750 hr following administration of Treatment A and Treatment B respectively. 
The T max ranged from 0.500 to 1.330 hr and 0.500 to 3.500 hr for Treatment A and 
Treatment B respectively. 
The exposure (Cmox and AUC0.96) of digoxin was not comparable for the Treatment A 
and Treatment B. The geometric mean Cmax was 1456.085 and 2254.118 ng/mL for 
Treatment A and Treatment B respectively. The geometric mean AUC0.96 was 
13473.043 and I 5996.644 ng.hr/mL for Treatment A and Treatment B respectively. 
Protocol No. C-CMP-SPI-001 
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Page 46 of64 
I 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
Drug-Drug Interaction (DDI) 
Statistical analysis was performed to assess the DOl as mentioned in Section 9.7. I. 
Geometric means, Geometric mean ratio and 90% Confidence intervals for Treatment 
A and Treatment B are provided in Table 9. The 90% confidence intervals of the 
geometric mean ratio (Treatment A I Treatment B) for Cmax and AUC0.96 were not 
within standard BE limits. 
Table 11 Summary of Statistical Analysis of Ln-transformed Pharmacokinetic Parameters of 
digoxin 
PK 
Geometric Least Square Means and It's Ratio 
(Treatment A I 
ISCV 
90%CI 
Power 
Parameters 
(Unit) 
Treatment A 
Treatment B 
Treatment B) 
(%) 
(%) 
(%) 
Cmax 
1456.085 
2254.118 
64.597 
40.07 
54.18% to 77.02% 
67.47 
(ng/mL) 
AU Co_,, 
13473.043 
15996.644 
84.224 
18.56 
77.45% to 91.59% 
99.56 
(ng.hr/mL) 
Treatment A: LANOXIN® (digoxin) USP 250 meg (substrate drug) 
Treatment B: LANOXIN® (digoxin) USP 250 meg + Spironolactone Oral Suspension 100 mg 
(Carospir® Oral Suspension 20 mL of25 mg /5 mL) 
Cmax and AUCo-96: 
The Treatment A was compared to the Treatment B with respect to the 
pharmacokinetic variables Cmax and AUC0•96 for digoxin using an analysis of variance 
with Treatment, period, sequence and subject nested within sequence effects after a 
logarithmic transformation of the data. Point estimates and 90% confidence intervals 
for the "Treatment A I Treatment B" mean ratios of these variables were calculated. 
Table 12 Summary Statistics for Untransformed Urine PK Parameters of digoxin Per 
Treatment 
Treatment 
Statistics 
Renal clearance 
unchanged drug excreted in urine 
(CLR)/Percent Recovered 
(fe)/ Amount Recovered 
N 
28 
28 
Mean 
54.687 
136717.72 
-< 
SD 
29.158 
72895.492 
-
c: 
Min 
22.180 
55449.800 
" 
E 
Median 
46.111 
115277.98 
., 
~ 
Max 
147.642 
369104.30 
f-
G. Mean 
49.042 
122606.02 
G.mean%CV 
48.257 
48.257 
Protocol No. C-CMP-SPl-001 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
Treatment 
Statistics 
Renal clearance 
unchanged drug excreted in urine 
(CLR)/Pcrcent Reconred 
(fc)/ Amount Recovered 
N 
28 
28 
Mean 
53.378 
133446.07 
o:l 
SD 
21.256 
53141.044 
-
c: 
Min 
21.641 
54103.200 
(l) 
E -
Median 
51.185 
127962.08 
"' 
(l) 
. 
... 
Max 
95.602 
239003.90 
r 
G. Mean 
49.410 
123523.87 
G.mean%CV 
42.201 
42.201 
Treatment A: LANOXIN® (digoxin) USP 250 meg (substrate drug) 
Treatment B: LANOXIN® (digoxin) USP 250 meg + Spironolactone Oral Suspension I 00 mg 
(Carospir® Oral Suspension 20 mL of25 mg I 5 mL) 
The Renal clearance (CLR)/Percent Recovered and unchanged drug excreted in urine 
(fe)/ Amount Recovered of digoxin was comparable for the Treatment A and 
Treatment B. The geometric mean Renal clearance (CLR)/Percent Recovered was 
49.042 and 49.410 for Treatment A and Treatment B respectively. The geometric 
mean unchanged drug excreted in urine (fe)/ Amount Recovered was 122606.02 and 
123523.87 for Treatment A and Treatment B respectively. 
11.4.2 Statistical I Analysis Issues 
Not applicable 
11.4.2.1 Adjustments for Covariates 
There were no covariate adjustments made during statistical analysis. 
11.4.2.2 Handling of Dropouts or Missing Data 
Pharmacokinetic analyses included data from samples of subjects who completed 
both study periods. 
The 90% confidence intervals are based on those subjects who completed both the 
periods ofthe study. 
11.4.2.3 Interim Analyses and Data Monitoring 
Not applicable. 
11.4.2.4 Multicentre Studies 
This was a single center study. 
Protocol No. C-CMP-SPJ-001 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
11.4.2.5 Multiple Comparison/Multiplicity 
Not applicable 
11.4.2.6 Use of an "Efficacy Subset" of Subjects 
Not applicable 
11.4.2. 7 Active- Control Studies Intended to Show Equivalence 
Not applicable 
11.4.2.8 Examination of Subgroups 
Not applicable 
11.4.3 Tabulation oflndividual Response Data 
Confidential 
The individual concentration data of digoxin was provided in Appendix 16.2.6. 
11.4.4 Drug Dose, Drug Concentration, and Relationships to Response 
Not applicable 
11.4.5 Drug-Drng and Drug-Disease Interactions 
Not applicable 
11.4.6 By- Subject Displays 
Individual plasma Concentrations Versus Time (Linear plots) for digoxin was 
provided in Appendix 16.2.6. 
11.4. 7 Pharmacokinetic Conclusions 
The % Treatment A I Treatment B ratio of digoxin was 64.597% and 84.224% for 
Cmax and AUCo.96 respectively. The lower and the upper limits at 90% confidence 
interval were 54.18% - 77.02% and 77.45% - 91.59% for Cmax and AUC0.96 
respectively, which is not within the standard equivalence limit of 80.00-125.00%. 
Based on the above results presence of drug-drug interaction is established between 
digoxin and spironolactone. 
By comparing Cmax and AUCo-96 plasma values of Treatment A and Treatment B, we 
conclude that these values were increased by 35% and 16% respectively for 
Treatment B 
The Renal clearance (CLR)/Percent Recovered and unchanged drug excreted in urine 
(fe)/ Amount Recovered of digoxin was comparable for the Treatment A and 
Treatment B. The geometric mean Renal clearance (CLR)/Percent Recovered was 
49.042 and 49.410 for Treatment A and Treatment B respectively. The geometric 
mean unchanged drug excreted in urine (fe)/ Amount Recovered was 122606.02 and 
123523.87 for Treatment A and Treatment B respectively. 
Protocol No. C-CMP-SPI-001 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
By comparing these values, we conclude that there is not much difference between 
Treatment A and Treatment B, with respect to Renal clearance (CLR)/Percent 
Recovered and unchanged drug excreted in urine (fe)/ Amount Recovered. 
Protocol No. C-CMP-SPl-001 
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Clinical Study Repmt for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
12. 
SAFETY EVALUATION 
12.1 
EXTENT OF EXPOSURE 
On Day 6, subjects were on fast for I 0.00 hours prior to dose administration and for 
4.00 hours post dose in each study period. Subjects were administered a single dose 
of either Treatment A or Treatment B as per randomization scheme with about 
240 mL of water for the subjects who were assigned A; 120 mL for LANOXIN" 
(digoxin) USP 250 meg and 120 mL for Spironolactone Oral Suspension 100 mg 
(Carospir" Oral Suspension 20 mL of 25 mg I 5 mL) for the subjects who were 
assigned B, at ambient temperature in sitting position in each study period. Oral 
cavity check was done immediately after drug administration to assess the 
compliance to this procedure. 
Total 28 subjects had completed the clinical phase of the study successfully. Plasma 
and urine samples of 28 subjects were analyzed and plasma and urine concentration 
data of all 28 subjects was considered to draw statistical conclusion. 
The duration of clinical phase was 39 days, including the washout period of 28 days 
between each study period. 
12.2 
ADVERSE EVENTS (AEs) 
12.2.1 Brief summary of adverse events 
There were no adverse events reported in this study. 
12.2.2 Display of adverse events 
There were no adverse events reported in this study. 
12.2.3 Analysis of Adverse Events 
There were no adverse events reported in this study. 
12.2.4 Listing of Adverse Events by Subject 
There were no adverse events reported in this study. 
12.3 
DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER 
SIGNIFICANT ADVERSE EVENTS 
There were no deaths or serious adverse events reported in this study. 
12.3.1 Listing of Deaths, other Serious Adverse Events and Other Significant Adverse 
Events 
Not applicable 
12.3.1.1 Deaths 
Not applicable 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
12.3.1.2 Other Serious Adverse Events 
Not applicable 
12.3.1.3 Other Significant Adverse Events 
Not applicable 
Confidential 
12.3.2 Narratives of Deaths, Other Serious Adverse Events and Certain Other 
Significant Adverse Events 
Not applicable 
12.3.3 Analysis and Discussion of Deaths, Other Serious Adverse Events and Other 
Significant Adverse Events 
Not applicable 
12.4 
CLINICAL LABORATORY EVALUATION 
12.4.1 Listing oflndividual Laboratory Measurements by Subject 
The individual laboratory measurements of each subject were given in 
Appendix 16.2.8. 
12.4.2 Evaluation of Laboratory Parameter 
12.4.2.1 Laboratory Values over Time 
The screening clinical laboratory investigations included hematology, serum 
biochemistry, serology and urine analysis as detailed in the protocol. The hematology 
(except blood grouping and Rh typing) and biochemistry (except random blood 
sugar) investigations done at screening were repeated at the end of the study. 
12.4.2.2 Individual Subject Change 
Not applicable 
12.4.2.3 Individual Clinically Significant Abnormalities 
For individual clinically non significant abnormalities refer to Table 16 m 
section 14.3.4. 
12.5 
VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS 
RELATED TO SAFETY 
Subjects were monitored for safety and tolerability during the entire study. The 
subject's Clinical examination along with vital signs (seated blood pressure, radial 
pulse rate and oral/aural temperature) were measured during check-in and check-out 
of each period. 
Clinical examination was done on prior to dosing on Day 06 in each study period. 
Oral/aural temperature was measured prior to dosing in each study period. 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Con tidential 
Vital parameters - seated blood pressure and radial pulse rate were measured at prior 
to dosing, 1.00, 3.00, 5.00 and 11.00 hours post dose in each period from Day I to 
Day 5, and from Day 6 to Day 9, vitals were measured prior to dosing, at 1.00, 2.00, 
3.00, 5.00, 8.00 and 11.00 hours post dose in each period. 
Note 
• 
On Day 6 the Vital signs (i.e. up to 3.00 hours post dose) was performed at bed 
side. 
• 
From day 1 to Day 5, subjects who were randomized to treatment A, the vitals 
were checked at 5.00 hours post dose. 
ECG was performed at 1.00 and 3.00 hours post dose in each period on Day 6, before 
period II check-in for subject study eligibility and at check-out of each period of the 
study. 2D echo was performed at the time of screening. 
In each study period creatinine clearance and serum potassium levels were measured 
on Day 05 for the dosing eligibility of the subjects. 
The screening clinical laboratory investigations included hematology, serum 
biochemistry, serology and urine analysis as detailed in the protocol. The hematology 
(except blood group and Rh typing) and biochemistry (except random blood sugar) 
investigations done at screening were repeated at the end of the study. 
12.6 
SAFETY CONCLUSIONS 
There were no adverse events reported in this study. 
Space left blank intentionally. 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
13. 
DISCUSSION AND OVERALL CONCLUSIONS 
This was an open label, balanced, randomized, single-dose, two-treatment, two-
sequence, two-period, crossover, drug-drug interaction study in healthy adult human 
subjects under fasting condition. 
This study was conducted in compliance with the final protocol, the applicable 
International Conference on Harmonization Guidelines for Good Clinical Practice 
(GCP), the relevant sections of Good Laboratory Practice (GLP), local laws and 
regulations (ICMR Guidelines on Biomedical Research, Schedule Y (amended 
version, 2014) of CDSCO (Central Drugs Standard Control Organization), relevant 
sections of Drugs and Cosmetics (First Amendment) Rules 2013, CDSCO 
Bioavailability & Bioequivalence guidelines, applicable USFDA guidelines, the 
provisions of Declaration of Helsinki (Brazil, October 20 13) and applicable in- house 
SOP's. 
The primary objective of this study was to characterize the pharmacokinetic profile of 
Digoxin (substrate drug) in the presence and absence of spironolactone (perpetrator) 
in healthy adult human subjects under fasting condition. 
The secondary objective of this study was 
• 
To assess whether there is a drug-drug interaction with concomitant use of 
spironolactone. 
• 
To measure renal clearance (CLR)/Percent Recovered and unchanged drug 
excreted in urine (fe)/ Amount Recovered for digoxin in the presence and 
absence of spironolactone (perpetrator) in healthy adult human subjects under 
fasting condition 
• 
To monitor safety of the subjects in drug-drug interaction study 
The clinical part of the study was conducted in 28 subjects and the plasma samples 
and urine samples were sent to Bioanalytical department, ClinSync Clinical Research 
Pvt. Ltd., Hyderabad, where the bioanalysis was performed using validated 
LCMS/MS method. The details have been presented in a separate Bioanalytical 
Report. The pharmacokinetic parameters Cmax, AUCo-96, and T mox for digoxin in 
plasma, Renal clearance (CLR) /Percent Recovered and Unchanged drug excreted in 
urine (fe )/Amount Recovered in urine were obtained using non-compartmental 
analysis (WinNonlin, version 8.1, Pharsight Corporation, USA). All statistical 
analyses were performed using SAS® version 9.3 (SAS Institute Inc., Cary, NC, 
USA). 
Sampling was done up to 96.00 hours such that the plasma concentration and urine 
samples could be measured for adequately profiling the phannacokinetics of the 
product and study periods were separated by a washout period of 28 days for 
Protocol No. C-CMP-SPI-001 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
complete elimination of the product substance. The pharmacokinetic and statistical 
analysis was done on all the 28 subjects. 
The median time to reach peak plasma concentration (Tma,) for digoxin was 0.750 hr 
and 0.750 hr following administration of Treatment A and Treatment B respectively. 
The T max ranged from 0.500 to 1.330 hr and 0.500 to 3.500 hr for Treatment A and 
Treatment B respectively. 
The exposure (Cmax and AUCo.96) of digoxin was not comparable for the Treatment A 
and Treatment B. The geometric mean Cmax was 1456.085 and 2254.118 ng/mL for 
Treatment A and Treatment B respectively. The geometric mean AUC0.96 was 
13473.043 and 15996.644 ng.hr/mL for Treatment A and Treatment B respectively. 
The intra-subject variability of digoxin for Cmax and AUC0.96 was 40.07% and 18.56% 
respectively. 
Absence of drug-drug interaction would be established if the 90% confidence interval 
for the ratio of population geometric means between two treatments (A and B), based 
on log-transformed data, present in the equivalence limits of80.00- 125.00% for Cmax 
and AUCo-96· 
The % Treatment A I Treatment B ratio of digoxin was 64.597% and 84.224% for 
Cmax and AUCo-96 respectively. The lower and the upper limits at 90% confidence 
interval were 54.18% - 77.02% and 77.45% - 91.59% for Cmax and AUC0•96 
respectively, which is not within the standard equivalence limit of 80.00-125.00%. 
Based on the above results presence of drug-drug interaction is established between 
digoxin and spironolactone. 
By comparing Cmax and AUCo-96 plasma values of Treatment A and Treatment B, we 
conclude that these values were increased by 35% and 16% respectively for 
Treatment B. 
The Renal clearance (CLR)/Percent Recovered and unchanged drug excreted in urine 
(fe)/ Amount Recovered of digoxin was comparable for the Treatment A and 
Treatment B. The geometric mean Renal clearance (CLR)/Percent Recovered was 
49.042 and 49.410 for Treatment A and Treatment B respectively. The geometric 
mean unchanged drug excreted in urine (fe)/ Amount Recovered was 122606.02 and 
123523.87 for Treatment A and Treatment B respectively. 
By comparing these values, we conclude that there is not much difference between 
Treatment A and Treatment B, with respect to Renal clearance (CLR)/Percent 
Recovered and unchanged drug excreted in urine (fe)/ Amount Recovered. 
Protocol No. C-CMP-SPI-001 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
14. 
TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED 
IN THE TEXT 
14.1 
DEMOGRAPHIC DATA 
Table 13: Summary Data of subjects enrolled and considered to establish DDI 
N ~ 28 (subjects enrolled and considered for the equivalence) 
Age (yrs) 
Height (ems) 
Weight (kg) 
BMI (kg!m2) 
Mean 
28.86 
169.21 
66.50 
23.27 
SD 
3.51 
5.79 
4.11 
1.68 
CV% 
12.18 
3.42 
6.18 
7.21 
Minimum 
20 
156 
60.50 
19.61 
Maximum 
35 
180 
74.20 
24.86 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Conlidential 
14.2 
PHARMACOKINETIC DATA 
Table 14: Plasma Pharmacokinetic Parameters of digoxin for Treatment A 
Subject 
Period 
Cmax 
AUC._,, 
Tmax 
(ng/ml) 
(hr)*(ng!ml) 
(hr) 
I 
2 
1231.789 
12257.410 
0.75 
2 
I 
1632.702 
12534.276 
1.00 
3 
2 
1119.346 
12320.487 
0.50 
4 
1 
1555.440 
14817.567 
0.75 
5 
2 
1200.204 
8632.172 
0.50 
6 
I 
1337.122 
15543.572 
0.50 
7 
2 
2734.608 
15261.849 
0.50 
8 
I 
1096.518 
13897.911 
1.00 
9 
2 
1508.190 
12497.649 
0.75 
10 
1 
1432.604 
16663.802 
0.75 
11 
2 
1259.124 
12280.198 
0.50 
12 
1 
1642.628 
12456.512 
0.75 
13 
1 
1653.681 
14957.186 
0.75 
14 
2 
1347.203 
13449.781 
1.33 
~···· 
15 
2 
1345.378 
14351.545 
0.75 
16 
I 
1427.040 
12256.029 
0.75 
17 
1 
1326.221 
14119.301 
0.75 
18 
2 
2520.483 
12229.820 
0.75 
19 
1 
2174.565 
13430.909 
0.75 
20 
2 
2673.194 
17461.106 
0.50 
21 
I 
1135.270 
15705.494 
1.00 
22 
2 
1664.995 
10134.973 
0.50 
23 
2 
1043.906 
15889.401 
0.75 
24 
1 
1593.511 
11630.262 
0.75 
25 
1 
862.546 
17061.128 
0.75 
26 
2 
644.613 
9969.226 
1.00 
27 
2 
1857.810 
10781.939 
0.75 
28 
1 
1824.584 
21455.761 
0.75 
N 
28 
28 
28 
Mean 
1530.188 
13715.974 
0.744 
SD 
502.810 
2669.003 
0.195 
Min 
644.613 
8632.172 
0.500 
Median 
1429.822 
13440.345 
0.750 
Max 
2734.608 
21455.761 
1.330 
Geometric Mean 
1456.085 
13473.043 
0.721 
CV% Geometric Mean 
32.993 
19.431 
25.996 
-~ 
Protocol No. C-CMP-SPI-00 l 
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Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Conlidential 
Table 15: Plasma Pharmacokinetic Parameters of digoxin for Treatment B 
Subject 
Period 
Cmax 
AUCo.96 
Tmax 
(ng/ml) 
(hr)*(ng/ml) 
(hr) 
I 
1 
2313.039 
12837.781 
0.50 
2 
2 
2309.434 
14268.044 
0.75 
3 
1 
2571.660 
17455.541 
0.50 
4 
2 
539.707 
6373.657 
3.50 
5 
I 
2395.355 
14545.854 
0.75 
6 
2 
2689.089 
18584.836 
0.75 
7 
I 
1587.620 
12877.001 
1.33 
8 
2 
2702.405 
19406.321 
0.75 
9 
I 
3367.439 
18282.739 
1.00 
IO 
2 
2044.626 
I8327.5II 
1.00 
I I 
1 
2984.589 
I4949.542 
0.50 
I2 
2 
2770.338 
20020.I83 
1.00 
I3 
2 
2551.554 
I 7133.898 
1.00 
14 
I 
2059.I85 
I7I68.285 
0.75 
I5 
I 
26I4.952 
I 7022.3I6 
0.50 
16 
2 
2224.220 
I7944.812 
1.00 
I7 
2 
8I6.I05 
1 I77l.090 
1.33 
18 
1 
2361.896 
13348.064 
0.75 
I9 
2 
3075.660 
I7479.894 
0.50 
20 
1 
5044.130 
23997.624 
0.50 
2I 
2 
2807.843 
17652.I44 
0.75 
22 
1 
I618.290 
ll21 J.37I 
0.75 
23 
1 
3399.330 
22551.024 
0.75 
24 
2 
I536.9I9 
12I57.027 
0.75 
25 
2 
3545.I95 
22764.006 
0.50 
26 
I 
I726.667 
I6I57.I83 
1.00 
27 
I 
2014.773 
13215.736 
0.75 
28 
2 
2449.4I5 
23938.5!0 
1.33 
N 
28 
28 
28 
Mean 
2432.908 
I655J.500 
0.901 
SD 
870.562 
4I08.500 
0.569 
Min 
539.707 
6373.657 
0.500 
Median 
2422.385 
I715J.09I 
0.750 
Max 
5044.130 
23997.624 
3.500 
Geometric Mean 
2254.118 
I5996.644 
0.8!0 
CV% Geometric Mean 
45.789 
28.453 
44.3!0 
Protocol No. C-CMP-SPI-001 
Confidential 
Page 58 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
Table 16: Urine Pharmacokinetic Parameters of digoxin for Treatment A 
Subject 
Period 
Renal clearance (CLR)/Percent 
unchanged drug excreted in 
Recovered 
urine (fe)/ Amount Recovered 
I 
2 
34.631 
86577.250 
2 
I 
33.729 
84321.800 
3 
2 
147.642 
369104.30 
4 
I 
40.035 
100086.65 
5 
2 
44.327 
110818.30 
6 
I 
23.771 
59428.600 
7 
2 
69.431 
173577.70 
8 
I 
47.895 
119737.65 
9 
2 
51.154 
127884.90 
10 
I 
39.269 
98171.600 
II 
2 
129.333 
323333.50 
12 
I 
43.727 
109317.10 
13 
I 
50.636 
126591.05 
14 
2 
41.026 
102565.70 
15 
2 
79.524 
198809.40 
16 
I 
27.638 
69094.500 
17 
I 
42.759 
106897.30 
18 
2 
72.921 
182302.70 
19 
I 
33.563 
83908.400 
20 
2 
83.953 
209883.35 
. 
21 
I 
31.465 
78661.400 
22 
2 
61.481 
153703.00 
23 
2 
57.658 
144144.60 
24 
I 
22.180 
55449.800 
25 
I 
35.214 
88036.050 
26 
2 
58.572 
146429.75 
27 
2 
78.807 
197018.60 
28 
I 
48.896 
122241.10 
N 
28 
28 
Mean 
54.687 
136717.72 
SD 
29.158 
72895.492 
Min 
22.180 
55449.800 
Median 
46.111 
115277.98 
Max 
147.642 
369104.30 
Geometric Mean 
49.042 
122606.02 
CV% Geometric Mean 
48.257 
48.257 
Protocol No. C-CMP-SP!-001 
Confidential 
Page 59 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
Table 17: Urine Pharmacokinetic Parameters of digoxin for Treatment B 
Subject 
Period 
Renal clearance (CLR)/Percent 
unchanged drug excreted in 
Recovered 
urine (fe)/ Amount Recovered 
I 
I 
51.134 
127834.30 
--
--
2 
2 
82.111 
205276.25 
3 
I 
92.243 
230606.45 
4 
2 
33.465 
83662.300 
5 
1 
24.256 
6064l.l50 
6 
2 
55.153 
137883.20 
7 
1 
21.641 
54103.200 
8 
2 
85.335 
213337.10 
9 
1 
58.284 
145709.60 
10 
2 
81.090 
202725.60 
II 
I 
40.858 
102145.85 
12 
2 
60.708 
151770.10 
13 
2 
42.000 
104998.80 
14 
I 
36.688 
91719.900 
15 
I 
28.858 
72144.000 
16 
2 
50.049 
125121.50 
17 
2 
95.602 
239003.90 
18 
I 
40.477 
101191.60 
19 
2 
53.560 
133899.30 
20 
I 
51.236 
128089.85 
21 
2 
59.550 
148874.30 
22 
I 
39.662 
99154.000 
23 
I 
56.615 
141538.50 
24 
2 
30.860 
77149.600 
25 
2 
88.821 
222053.60 
26 
I 
35.062 
87654.650 
27 
I 
38.638 
96595.200 
28 
2 
60.642 
151606.10 
N 
28 
28 
Mean 
53.378 
133446.07 
SD 
21.256 
53141.044 
Min 
21.641 
54103.200 
Median 
51.185 
127962.08 
Max 
95.602 
239003.90 
Geometric Mean 
49.410 
123523.87 
CV% Geometric Mean 
42.201 
42.201 
Protocol No. C-CMP-SPI-001 
Confidential 
Page 60 of64 


Clinical Study Rep011 for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
14.3 
SAFETY DATA 
14.3.1 Displays of Adverse Events 
There were no adverse events reported in this study. 
14.3.2 Listing of Deaths, Other Serious and Significant Adverse Events 
There were no deaths or serious adverse events in this study. 
Confidential 
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse 
Events 
There were no deaths, other serious and certain other significant adverse events 
recorded during the study. 
14.3.4 Abnormal Laboratory Value Listing (each Subject) 
Table 18: Abnormal Laboratory Value Listing 
Parameter 
Sub. No. 
Pre-Study 
Post Study 
03 
--
12.7L 
06 
--
12.8 L 
07 
--
12.9L 
10 
--
12.8 L 
Hematology 
14 
12.8 L 
--
17 
---
12.7 L 
23 
---
12.7L 
26 
---
12.8L 
r-------------·---· ------··- ··-···-·4.4 L 
05 
RBC Count 
4.4L 
09 
---
Remarks 
NS 
NS 
NS 
NS 
NS 
NS 
NS 
NS 
NS 
NS 
L= lower than normal Range, H: Higher than normal range, CS: Clinically Significant NS: Not Significant 
Protocol No. C-CMP-SPl-00 I 
Confidential 
Page61 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
ConJidcntial 
15. 
REFERENCE LIST 
1. Approved 
Protocol 
(Protocol 
No. 
C-CMP-SPI-001; 
Version 
02, 
date: 
07 Aug 2018) 
2. Amendment No.:Ol Date: 19 Dec 2018 
3. ICH E3- Structure and content of Clinical Study Report 
Protocol No. C-CMP-SPI-00 I 
Confidential 
Page 62 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
16. 
APPENDICES 
16.1 
STUDY INFORMATION 
16.1.1 
Protocol and Protocol Amendments 
16.1.2 
Sample case report form 
Confidential 
16.1.3 
List of IEC members along with approval letter- Representative written 
information for subject and sample informed consent documents 
16.1.4 
List and description of investigators and other important participants in the 
study, including brief CVs or equivalent summaries of training and experience 
relevant to the performance of the clinical study 
16.1.5 
Signatures of Principal or Coordinating Investigator(S) and the key personnel 
involved in the conduct of the study 
16.1.6 
Listing of subjects receiving test drug(s)/investigational product(s) from 
specific batches, where more than one batch was used 
16.1. 7 
Randomization Schedule 
16.1.8 
Audit certificates 
16.1.9 
Documentation of statistical methods 
16.1.10 Documentation of inter laboratory standardization methods and quality 
assurance procedures (If Used) 
16.1.11 Publications based on the study 
16.1.12 Important publications referenced in the report 
16.2 
SUBJECT DATA LISTINGS 
16.2.1 
Discontinued subjects 
16.2.2 
Protocol deviations 
16.2.3 
Subjects excluded from the efficacy analysis 
16.2.4 
Demographic data 
16.2.5 
Compliance and/or drug concentration data 
16.2.6 
Individual efficacy response data 
16.2.7 
Adverse event listings 
16.2.8 
Listing of individual laboratory measurements by subject when required by 
regulatory authority 
Protocol No. C-CMP-SPI-00 I 
Confidential 
Page 63 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
16.3 
CASE REPORT FORMS 
16.3.1 
CRFs for deaths, other serious adverse events and withdrawals for AE 
16.3.2 
Other CRFs submitted 
16.4 
INDIVIDUAL SUBJECT DATA LISTINGS 
16.5 
BIOANAL YTICAL REPORT 
Protocol No. C-CMP-SPI-001 
Confidential 
Page 64 of64 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
16.0 APPENDICES 
Protocol No.: C-CMP-SPJ-00 I 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
16.1 STUDY INFORMATION 
Protocol No.: C-CMP-SPI-00 I 


Clinical Study Repm1 for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
16.1.1 PROTOCOL AND PROTOCOL AMENDMENTS 
Protocol No.: C-CMP-SPI-00 I 


Protocol tOr Drug-Drug Interaction Swdy of Spironolactone and Digo\.in (Fasting 
Condition) 
Conf1dcntial 
TITLE PAGE 
Protocol Title 
An open label, balanced, randomized, single-dose, two-treatment, two-seq uencc, two-
period, crossover oral drug-drug interaction study of spironolactone (perpetrator) and 
Digoxin (substrate drug) in healthy adult human subjects under fasting condition. 
Protocol No. 
Version 
Supersedes version 
Document status 
Content Final Date 
Sponsor 
CRO& 
Clinical Study site 
C-CMP-SPJ-00 I 
02 
OJ, !3 Feb 2018 
Final 
07 Aug20!8 
CMP Development, LLC. 
PO Box 147 
8026 US Highway 264A 
Farmville, NC 27828 
Telephone: (800)227-6637 
ClinSync Clinical Research Pvt. Ltd. 
#4-1-1, Hayatlmagar, 
Hyderabad, Telangana- 501505, 
India. 
The. e?~ie.nx~ ,ofihis (!orl!lnt'fll 'We ~?Nz'~<e'iti~l'a'!cl.P(()Pri'etr.IJ:.to• r:iif!Syn,c.· (.:li'!fcql 
Researi:l:z Pw .. I,td, iAny. imau!lwriz-ed uie, aiscloswe ·• qr •reproduction Is stri!;tly 
'- ._-, ..• •'' · ..... ,- -
- -,'- --- -_, 
:· . .• 
', . . 
- - -;, ' ·'' ', '-·' <..-:-:., ' - -, 
______ ,_' --. -.,·. __ ... ','-
-- .---- -,-.;-- .,_- ,_. -.-- _- -, 
·: 
,-, '' ' ' 
' 
___ .,' 
Pl-00!; Version 02: Date: 07 Aug 2018 
Page I of83 


Protocol for Drug-Drug Intcruction Study of Spironolactone and Digoxin (Fastmg 
Condition) 
ConlidentJal 
Investigator's Declaration 
I, the undersigned, have read and understood this protocol and hereby agree to 
conduct the study in accordance with this protocol and to comply with all the 
requirements regarding the obligations of investigators and all other pettinent 
requirements of the 'Good Laboratory Practice' ICH (Step 5) 'Guidance on Good Clinical 
Practice' and applicable regulatory requirements including applicable US FDA 
requirements for conduct of clinical studies. 
I agree to comply with all relevant SOPs required for the conduct of this study. I 
further agree to ensure that all associates assisting in the conduct of this study are 
infonned regarding their obligations. 
Signature 
Dr. Roopali K. Somani, MD Pharmacology 
Principal Investigator 
Clinical Pharmacology Department, 
ClinSync Clinical Research Pvt. Ltd. 
Date 
#4-1-1, Hayathnagar, Hyderabad, Telangana- 501505, India 
Phone No.: +91-40-24203001/2/3 
Fax No.: +91-40-24203000. 
r
\t,t;<;4 VI i'!STITUTIONAL 
i f' · ICS COMMITTEE 
!PtPPH:OVED 
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
Page 2 of83 


~/CiinSync 
Protocol fc>r Drug-Drug Interaction Study of Spmmolactonc and Digoxin (Fasting 
Condition) 
Confidential 
Signature 
Mr. Chirag Khatri, M. Sc 
Bioanalytical Investigator, 
ClinSync Clinical Research Pvt. Ltd. 
Signature 
Dr. Jaganmohan S, M. Phann, Ph.D, PDF 
Phannacokinetic Investigator, 
ClinSync Clinical Research Pvt. Ltd. 
Signature 
Mr. Tushar Shinde, M.Sc 
Statistical Investigator, 
ClinSync Clinical Research Pvt. Ltd. 
Signature 
Mr.Madhu Sudhan K V, M.Sc, MBA 
In charge - QA & RA, 
ClinSync Clinical Research Pvt. Ltd. 
VASWi INSTfTUTION 
E"r· .. -s 
Al 
I "'··· COMMITTEE 
t.~PPROVED 
of- A-4 2-o 1 % 
Date 
.:2--V 13 
Date 
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
Page 3 of83 


Protocol for Drug-Drug Intcrt1ction Study of Spironolactone and Digoxin (Fasting 
Condition) 
Confidential 
"--~---
" -- --------------~-~-
Sponsor's Approval 
I, on behalf of CMP Development LLC, USA, have read, understood and approve this 
protocol. I agree to comply with all requirements regarding the obligations of sponsor and 
all other pertinent requirements of the 'Guidance on Good Laboratory Practice', ICH 
(Step 5) 
1Guidance on Good Clinic-al Practice' and applicable regulatory requirements 
including applicable US FDA requirements for conduct of clinical studies. 
Autl1orized Signatory 
Gerald Sakowski 
Chief Executive Officer 
CMP Development LLC 
PO Box 147 
8026 US Highway 264A 
Farmville, NC 27828 
Telephone: (800)227-6637 
Date 
Protocol No.: C-CMP-SPI-00 I; Version 02; Date: 07 Aug 2018 
\'AS/',\/ I !N: "!TlJTfONAL 
ETHICS COMMITTEE 
P'PROVFD 
·-,~ 
·' 
Page 4 of83 


Proh)Col f()r Drug-Drug Interaction Study of Spironolactone a11d Digox111 {Fasting 
Condition) 
Confidential 
TABLE OF CONTENTS 
TITLE PAGE ...................................... . 
. •.....•.•....•.••..•...•.•..• ·····································I 
Investigator's Declaration ................................................................................................... 2 
Sponsor's Approval .............................................................................................................. 4 
TABLE OF CONTENTS ................................................................................................... 5 
SYNOPSIS ........................................................................................................................... 9 
LIST OF ABBREVIATIONS AND SYMBOLS .............................................................. 14 
1 
STUDY INFORMATION ........................................................................................... 16 
2 
BACKGROUND INFORMATION .......................................................................... 20 
2.1 
Spironolactone (CaroSpir") ............................................................................. 22 
2.1.1 
Description of Investigational Product.. .......................................... 22 
2.1 .2 
Phannacology .................................................................................. 22 
2.1 .3 
Phannacokinetics ............................................................................. 22 
2.1.4 
Drug Interactions ............................................................................. 23 
2. I .5 
Indications ....................................................................................... 2 5 
2 .!. 6 
Adverse Effects ............................................................................... 2 5 
2.1.7 
Dosage & Administration, Contraindications and Warnings .......... 26 
2.2 
Digoxin (LANOXIN") ..................................................................................... 28 
2.2.1 
Description of Investigational Product ............................................ 28 
2.2.2 
Phannacology .................................................................................. 28 
2.2.3 
Phannacokinetics ............................................................................. 29 
2.2.4 
Drug Interactions ............................................................................. 30 
2 .2.5 
Indications ....................................................................................... 31 
2.2. 6 
Ad verse Effects ............................................................................... 3 I 
2.2. 7 
Dosage & Administration, Contraindications and Warnings .......... 33 
3 
STUDY OBJECTIVES AND PURPOSE ................................................................... 36 
3 .I 
Objectives ......................................................................................................... 3 6 
3.2 
Purpose ............................................................................................................. 36 
4 
STUDY DESIGN ....................................................................................................... 37 
4.1 
Number of Subjects .......................................................................................... 37 
4.2 
Randomization ................................................................................................. 3 7 
4.3 
Blinding .......................................................................... .. 
. ..................... 37 
r~·;~\~ N 
; 
L.HIL~NoE C MP-SPI-001; Version 02; Date: 07 Aug 2018 
~~~PROVED 
Page 5 of83 


Protocol tt)r Drug-Drug Interaction StuJy of Spironolactone and Digoxin (Fasting 
Condition) 
Contidcnlial 
4.4 
Housing and Washout period ............... . 
........ 37 
5 
INVESTlGA TIO~AL PRODUCTS ................................ . 
. ......... 37 
5.1 
Receipt, Storage and Accountability of Investigational Products .................... 38 
5.1.1 
Receipt of Investigational Products ................................................. 38 
5.1.2 
Storage of Investigational Products ................................................. 38 
5.1.3 
Accountability of Investigational Products ..................................... 38 
5. 1.4 
Dispensing ....................................................................................... 38 
5.1.5 
Handling of Unused Investigational Products ................................. 39 
5.1.6 
Retention of Samples ....................................................................... 39 
6 
TREATMENT OF SUBJECTS ................................................................................... 39 
6.1 
Treatments to be administered ......................................................................... 39 
6.2 
Drug Administration ........................................................................................ 40 
6.3 
Sampling Schedule ........................................................................................... 41 
6.4 
Sampling Procedure ......................................................................................... 41 
6.5 
Blood Loss ....................................................................................................... 43 
6. 6 
Diet and Water ................................................................................................. 44 
6. 7 
Total duration of subject participation in the study ........................................ .44 
6.8 
Maintenance of Study Treatment Randomization Schedule ............................ 45 
6.9 
Documentation of Study Activities .................................................................. 45 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. .45 
7.1 
Subject Inclusion Criteria ................................................................................. 45 
7.2 
Subject Exclusion Criteria ............................................................................... 46 
7.3 
Criteria for Discontinuation of the study ........................................................ .47 
7.4 
Tests to be performed before Check-in of the study ........................................ 47 
7.5 
Subject Withdrawal Criteria ............................................................................. 48 
7.5.1 
Procedures to Withdraw Subjects from the Investigational 
Product Treatment ........................................................................... 48 
7.5.2 
The Type and Timing of the Data to be collected for 
Withdrawn Subjects ......................................................................... 49 
7.5.3 
Replacement of Subjects ................................................................. 49 
7 .5.4 
The Follow-up for Subjects Withdrawn from Investigational 
Product Treatment ........................................................................... 49 
7.6 
Restrictions ....................................................................................................... 49 
r\f/\SA p r 
-.~J..,.. 
Diet .................................................................................................. 49 
I 
ET!flfOt~~ P-SP!-001; Version 02; Date: 07 Aug 2018 
Page 6 of83 
APPROVED 


Protocol 
fl:1r Drug-Drug 
Intcra~...·tion Study of SpirOJwlaL-·tunc and Digoxin (hlsting 
Cmdition) 
7.6.2 
7.6.3 
7.6.4 
Conildcnticli 
Posture ..... 
..... ,.,,.,,,,,.,,,,,,,,,,,,, , .......................... , .................. 50 
Medication .. 
.......................... 50 
Others ............................................. .. 
' .... 50 
8 
B IOANAL YTICA L PROCEDURES.................................................................... .. . 51 
8. I 
Method Description .......................................................................................... 5 I 
9 
P HARMACOKIN ETIC ASSESSMENTS .................................................................. 5 I 
I 0 STATISTICAL ANALYSIS ....................................................................................... 53 
1 0. I 
Number of subjects .......................................................................................... 53 
1 0.2 
Analysis of variance ......................................................................................... 53 
10.3 
Two one-sided test for bioequivalcnce ............................................................ 54 
I 0.4 
Power ............................................................................................................... 54 
I 0.5 
Ratio analysis ................................................................................................... 54 
I 0. 6 
Intra-Subject Variability .................................................................................. 54 
1 0. 7 
Criteria for evaluation ...................................................................................... 54 
It ASStSSMENT OF SAFETY .................................................................................... 55 
11. I 
Specification of Safety Parameters .................................................................. 55 
11 .2 
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters ........................................................................................................ 55 
11.3 
Handling and reporting of Adverse Events and Serious Adverse Events ........ 58 
11.4 
Type and Duration of the Follow-Up ofSubjects ............................................ 63 
I 1.5 
Criteria for the Termination of the Study ......................................................... 63 
I2 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .......................................... 63 
1 3 QUALITY ASSURANCE ........................................................................................... 64 
14 ETHICS ...................................................................................................................... 64 
14. 1 
lnsti tuti onal Ethics Committee ......................................................................... 64 
14.2 
Written Infom1ed Consent ............................................................................... 64 
14.3 
Audio Video Consent ....................................................................................... 65 
14.4 
Subject Pm1icipation Fee ................................................................................. 65 
15 DATA HANDLING AND RECORD KEEPING ....................................................... 66 
15. I 
Study Report and Documents .......................................................................... 66 
15.2 
Archiving ......................................................................................................... 66 
15.3 
Confidentiality of Data ..................................................................................... 66 
r
-~Li"L..E!)'JANCJNG AND INSURANCE ............................................................................. 6 7 
, VASAV 
!<;TT 
I Efl'~~(FJ«!;K1P SPI-00 J; Version 02; Date: 07 Aug 201 8 
Page 7 of 83 
!APPROVED 


) .~·-
\/; 
' 
Protocol ftH Drug-Drug lntcractwn Studv nf SpJronnlactunc and Digo.\in (Fast1ng 
Cnmhtion} 
C 'ontidcntial 
17 PUBLICATION POLICY .......................... . 
18 REFERENCES ............................................ .. 
19 APPENDICES ............................................... . 
.. ..... 68 
Appendix I: Schematic Diagram of Study Design ...................................................... 69 
Appendix II: Assessment schcd ulc .............................................................................. 70 
Appendix Ill: Diet Schedule Form .............................................................................. 72 
Appendix -IV: Laboratory Reference Ranges .............................................................. 81 
SPI-00 1: Version 02; Date: 07 Aug 2018 
Page 8 of83 


Protocol for Drug-Drug Interaction Study of Spirono!adol!C and Digoxin (Fasting 
Condition) 
Confidential 
SYNOPSIS 
j~1Cj(ic-~~-~-~ A~~;,en IabcL-b;lanccd-:-;=andomizcd. -siOgJe-dose:~"~~;::trcat;~;~;:;;~] 
I 
I two-sequence. two-period, crossover oral dmg-drug interaction , 
I 
study of spironolactone (perpetrator) and Digoxin (substrate drug) I 
i 
111 healthy adult human subjects under t[rsting condition. 
I 
I Objectives 
i Primmy objectives: 
--i 
' 
To characterize the phannacokinetic profile of Digoxin (substrate 
drug) in the presence and absence of spironolactone (perpetrator) in 
healthy adult human subjects under fasting condition. 
Study design 
Secondwy objective: 
• 
• 
• 
To assess whether there is a dmg-drug interaction with 
concomitant use of spironolactone. 
To measure renal clearance (CLR)iPercent Recovered and I 
I 
unchanged drug excreted in urine (fe)/ Amount Recovered for II 
digoxin in the presence and absence of spironolactone 
(perpetrator) in healthy adult human subjects under fasting I 
condition. 
i 
To monitor safety of the subjects in drug-drug interaction 
study. 
An open label, balanced, randomized, single-dose, two-treatment, ' 
I
, two-sequence, two-period, crossover, drug-drug interaction study in 
I
. healthy adult human subjects under fasting condition. 
Study Duration: 
i ' In each period, subjects will be housed in a climate-controlled 
environment from at least 11.00 hours before starting of Day I until 
the collection of 96.00-hour blood sample on Day 10. 
No. of Subjects: 28 healthy adult human subjects will be included 
in the study. Additionally, 04 stand-by subjects will be included in I 
, order to dose 28 subjects in petiod I. 
I 
'ashout Period: At least 28 days. 
! 
-SPI-001; Version 02; Date: 07 Aug 2018 
Page 9 of83 


Pro1ocol flx Drug-Drug Interaction Study of Spirnnolactnnc and D1goxin (Fasting 
Condition) 
Confidential 
==:;::===------ -··-===== 
! No. oflf,:ine & l:llootl~ampl~>: 
d---------1 
I Urine & Blood samples collection will be started afler the j 
J completion of dosing on Day 6. 
j 
J A total of 11 urine samples will be collected ti'om each subject in J 
/ e~ch study period: 
. 
. 
I 
J Unne samples wdl be collected at mtervals ol (0.00-1.00), ( 1.00-, 
[2.00), (2.00-4.00), (4.00-6.00), (6.00-8.00), (8.00-12.00), (12.00-1 
116.00), (16.00-24.00), (24.00-48.00), (48.00-72.00) and (72.00-~ 
I 96.00) hours post dose. 
I' Immediately out of the total volume of urine collected at each 
collection time interval, approximately 10 mL (2 x 5 mL aliquots) 1 
1
1 
of urine samples will be transferred into two pre-labeled containers / 
, for analysis. They will be stored at deep freezer maintained at / 
j-zooc or lower until dispatcherl from Clinical Unit to Bioanalytical i 
I 
Department for analysis. 
1 
I 
A total of 25 blood samples will be collected from each subject in 
each study period. Blood samples will be collected at pre-dose 
(0.00) and post dose at 0.25, 0.50, 0.75, 1.00, 1.33, 1.67, 2.00, 2.33, 
2.67, 3.oo, 3.5o, 4.oo, 5.oo, 6.oo, s.oo. 1o.oo, 12.oo. 16.oo. 24.00, 1 
, 36.00, 48.00, 60.00, 72.00 and 96.00 hours in each period. 
j 
Note: Blood samples up to 3 hours post dose will be collected at / 
bed side. 
j 
I Total Blood loss: The tc,tal blood loss per subject in the study will I 
I not exceed 292 mL for male/post-menopausal female subjects and .I 
f-:---.-,----;-+::2::-9_6_m_L_fi_or-:-:fe-:m-a
7
le. subjects of child bearing potential. 
1 
Investigational I Treatment (A): LANOXIN"' (digoxin) USP 250 meg (substrate 1 
Products 
1 drug). 
I Treatment (B): LANOXlN" (digoxin) USP 250 meg (substrate I 
. 
I 
j drug) + Spironolactone Oral Suspension 100 mg (Perpetrator; I 
/ Carospir' Oral Suspension 20 mL of 25 mg ! 5 mL of CMP / 
i Development LLC, USA.) 
I 
·---·~---·-------
: VASAVI 1 
FTH!Cfir£\)Jt'llilfg~~- MP-SPJ-001; Version 02: Date: 07 Aug 2018 
\ j(ROVED 
Page 10 of83 


Protocol t(n Drug-Drug Interaction Study of Spironoladt)nc and Digoxin (Fasting 
Condition) 
Contidcntial 
-- ···-------
I Drug ______ fSpironolactone Oral Susp-;;;;sion I 00 ·;;;g-(i>c;,;ctrator; c;rrospi?'] 
, Administration [ Oral Suspension 20 mL of 25 mg I 5 mL of CMP Development J 
I LLC, USA.) will be administered as a single dose fi·01n Day I to I 
/ Day 5 and Day 7 to Day 9, to the subjects who will be randomized I 
i to treatment ~ as per randor~1ization scheme. 
. 
1 
I. 
On Day 6, after ovem1ght lastmg of at least 10.00 hours, either of I 
treatment (A) or treatment (B) will be administered orally to the I 
/ subjects in sitting posture with 240 ± 2 mL of water, at ambient 
temperature as per the randomization scheme. After a washout J 
period of 28 days, the same procedure will be repeated during / 
period-H. 
I 
Subjects will be instructed not to chew or crush the tablet (for/ 
substrate drug) and swallow as a whole. 
, 
, Compliance for dosing will be assessed by a thorough check of the I 
oral cavity immediately after dosing. 
! 
A total of 240 ± 2 mL of water will be administered with 
1
1 
investigational products. However, for Treatment B, 120 mL of 
I 
water with 20 mL ofCaroSpir oral suspension and 120 mL of water/ 
' with one tablet of Lanoxin. 
I 
Instructions for CaroSpir oral suspension administration: 
I 
1. CaroSpir ora! suspension will be administered with a 
graduated syringe. 
2. 20 mL of 25 mg I 5 mL of Carospir" Oral Suspension will be 
loaded in the syringes well in advance prior to dosing on the I 
day of dosing. 
I 
3. The suspension in the syringe will be directly administered to I 
the subjects. 
I 
4. The syringe will be 1insed with water (approximately 10 mL 
1
1 
from 120 mL of dosing water) and will be administered to the , 
subjects. This procedure will be followed till the syringe is J 
free of the contents of the medication. Then the rcmainingJ 
Pro 
c<l'i':~hcse~L'§li¥-oo ; Version 02; Date: 07 Aug 2018 
~PP·ROVED 
Page II of83 


:i: 
Protocol fiJr Drug-Drug Intcradion Study of Sp1ronoLtclonc and Digt1xin (F:lsling 
Condition) 
~--
1 ' 
I Clinical Safety 
1 measures 
I 
I 
Bioanalytical 
procedure 
Confidential 
..--- -
i 
quantity of water (hom the 120 mL) will also be administered 
I 
to the subject. 
I
' 5. Drug administration will be carried out at the same dosing 
times tor all dosing days (i.e. from Day OJ to Day 09). 
I 6. From Day I to 5 and Day 7 to 9 the Standard Breakfast will be 
I 
served 0.50 hr (30 min) post dose. 
___ _ 
, Safety will be determined by no clinically significant deviation 
from nonnal in findings of medical history, physical examination, 
; electrocardiograms, vital signs, and clinical laboratory tests. 
! 
· A validated LC-MS/MS method will be used for quantification of 
digoxin in presence of spironolactone and canrenone in plasma. 
Unchanged drug excreted in urine for digoxin will be analyzed by 
1 using validated LC-MS/MS method. 
I 
PK P="'"" ~Prim.,'""""'"" 
I
. based on 
Secondary parameters 
plasma data 
l 
C.n"' and AUCo.96 
i Tmax 
! PK parameters 
based on urine 
I data 
I 
PK parameters 
' evaluation 
using 
WinNonlin 
Statistical 
analysis 
Renal clearance (CLR) /Percent Recovered 
Unchanged drug excreted in urine (fe)/ Amount Recovered 
Employing the estimated concentration vs. time profiles of digoxin 
using 
WinNonlin 
Software 
version 
6.4 
or 
above, 
the 
pharmacokinetic parameters will be calculated. 
Statistical analyses will be done using SAS" system for windows 
version 9.3 or above (SAS'' Institute Inc., USA). 
I 
The log-transfonned phannacokinetic parameters Cmax and AUCo-96 
will be analysed for Digoxin using ANOV A. The Intra subject CV, I 
Power, Ratio analysis, and its 90% Cl will be computed for log-
' transfonned pharmacokinetic parameters Cm" and AUCo.w, for 
digoxin. 
~ 
rv~ll~l~C.~T~~~~~~A=b=s=en=c=e==o=f=d=n=I=g=-d=ru==g=t=n=te=l=·a=c=tl=Ol=1=\=V-=!J=]=b=e==es=t=ab=l=!S=h=ed===lf==th=e==9=0=o/r=~~j----
~ ·,: '·_-~_.: 
__ cP: COMMl:);JE;L 
rofoc6l-No .. L> 
<.. 'l.-'i!:?OVED 
,, 
., 
':..· ~::;.;:::...::...=.::::::J 
MP-SPJ-001; Version02; Date: 07 Aug2018 
Page 12 of83 


ProllKol ft)r Drug-Drug Interac!Jon Study of Spironoladonc and Digoxin (Fasting 
Condition) 
(\)nfidcntial 
[ c~<;l uat:i o=,=, ==;=, =pcr:~~;~f._f;_o_r_t_h~e ,~a tJ~-~-~~;~~~l~~a-ti-,~-n -ge;;;,-c-triZ~_n_e_a_n;:~~~;;.~c:ll-~v-n_J_/_ 
/treatments (A and ll), based on log-transformed data, pres<:nt in the i 
J equivalence limits of80.00- 125.00% for c,,.,, and AUCo.q,,, 
I 
I 
I 
I 
' 
I 
I 
I Summary statistics of pharmaeokinetic profile of Digoxin 
i (substrate drug) in the presence and absence of spironolactone 
/ (perpetrator) will be provided based on plasma and urine data. 
Renal clearance (CLR)/Percent Recovered and unchanged drug 
excreted in urine (fc)/ Amount Recovered for digoxin will also be I 
j measured and provided as a supp01ting data (evidence). 
/ 
Protocol No.: C-CvlP-SPJ-00!; Version 02; Dale: 07 Aug 20!8 
Page 13 of83 


)··--"-' 
l < •. 
< 
I 
tJJ\ . 
""'"'~,: ... 
Protocol for Drug-Drug lnteract]()Jl Study of Spironolactone and Dignxin (Fasting 
Condition) 
Contidcntial 
LIST OF ABBREVIATIONS AND SYMBOLS 
0;0 
oc 
ADR 
AE 
ALT 
AN OVA 
AST 
AUCo-90 
BAIBE 
BLQ 
BMI 
BS 
CDS CO 
CLR 
Cmax 
COA 
CP 
CRF 
CSR 
CRO 
DDI 
ESR 
fe 
HBsAg 
llCV 
HIV 
hrlhrs 
lCD 
ICH 
ICMR 
ICU 
ID 
IEC 
IP 
IU 
Percentage 
Degree centigrade 
Adverse Drug Reaction 
Adverse Event 
Alanine Amino Transferase 
Analysis of Variance 
Aspartate Amino Transferase 
Area under the plasma concentration versus time curve trom time 0 
to the 96 hour time point concentration 
Bio-A vailability/Bio-Equivalence 
Below Limit of Quantification 
Body Mass Index 
Biostatistics 
Central Drugs Standard Control Organization 
Renal Clearance 
Maximum measured plasma concentration 
Ce1tificate of Analysis 
Clinical Phannacology 
Case Report Form 
Clinical Study Report 
Contract Research Organization 
Drug-Drug Interaction 
Etythrocyte sedimentation rate 
Unchanged drug excreted in urine 
Hepatitis B Surface Antigen 
Hepatitis C Vims 
Human Immunodeficiency Virus 
Hours 
lnfonned Consent Document 
lntemational Conference on Harmonization 
Indian Council of Medical Research 
Intensive Care Unit 
Identity Document 
Institutional Ethics Cmrunittee 
Investigational Product 
lntemational Unit 
-CMP-SP!-00!; Version 02: Date: 07 Aug 2018 
Page 14 of 83 


,--, ,···· 
' ; \. 
. 
; '-.r 
ProtoC<.)I f()r Drug-Drug Intewctinn Study of Spironolactone and Dtgoxin {Fastmg 
Condition) 
K2EDTA 
Kg 
LC-MS/MS 
Ln 
LOQ 
Ltd. 
M 
Meg 
Mg 
mL 
MSE 
MW 
No. 
NR 
OTC 
PIA view 
PI 
PK 
RBC 
Rh 
Rpm 
RPR 
SAE 
SAS 
SD 
SGOT 
SGPT 
SOP 
Tmax 
VORL 
WBC 
BhCG 
Di potassium Ethylene Diaminc Tetraacetic Acid 
Kilogram 
Liquid Chromatography tandem mass spectrometry 
Natural Logmithm 
Limit of Quantification 
Limited 
Missing samples 
Microgram 
Milligram 
Millilitre 
Mean Square En'Or 
Medical Writing 
Number 
Not reportable 
Over The Counter 
Posterior-Anterior view 
Principal Investigator 
Phannacokinetic 
Red Blood Corpuscles 
Rhesus 
Rotations per minute 
Rapid Plasma Reagin 
Serious Adverse Event 
Statistical Analysis System 
Standard Deviation 
Serum Glutamic Oxaloacetic Transaminase 
Senun Glutmnic Pyruvic Transaminase 
Standard Operating Procedure 
Time to achieve maximum plasma concentration 
Venereal Disease Research Laboratory 
White Blood Corpuscles 
Beta Human Choxionic Gonadotropin 
1· VASAV! :USTITUTIONAL 
I ETHICS COMMITTEE 
!,!\PPRO\IED 
;;,.,~~ 
Protocol No.: C-CMP-SPI-00!; Version 02; Date: 07 Aug 2018 
ContidcntJal 
Page 15 of83 


Protocol iiJr Drug-Drug 
Intl~r;tdion Study of Spironolal'tonc and Digoxm (Fasting 
Condition) 
Conlidcntial 
STuDY INFORMATION 
r>;:-;;t"(;"~~l Title, Protocolldcntif)i~iN~;;l-b~;-,·D~te andRcgnlator)~lls~ion--J 
. 
j : / An open lahel, halanced, randomized, single-dose, two- [ 
I 
. 
I / treatment, two-sequence. two-period, crossover oral drug-/ 
I Protocol Title 
I : dmg mteract10n study of spironolactone (peqwtrator) and J 
I 
I / 
Digoxin (substrate drug) in healthy adult human subjects / 
i under fasting condition. 
J 
1-cP::::r_o_to_c_o_l_N_u_n_Jb_e_r_-+-:-+ [,--:C:c:·:-:CMP-SPI-001, Version: 02 
-- --~ 
i Date 
: 07 Aug2018 
-----l 
I 
Regulatory 
Submission 
I: USFDA 
I 
Sponsor's Representative and Monitor 
Sponsor's 
Representative 
: Gerald Sakowski 
1 Chief Executive Ofticer 
I 
I 
I 
CMP Development LLC, 
PO Box 147 8026 US Highway 264A, 
' 
Sponsor's Medical Expert 
I 
i 
·-l 
Monitors other 
i Fannville, NC 27828 
i Telephone: (800)227-6637 
1 : 
Not Applicable 
' 
than Sponsor 
Sponsor's Medical 
1
, : / Dr. Kim A. Cook, M.D., M.S.P.H. 
Expert 
I Medical Director, 
I 
/ 
Kiel Laboratories Inc, 
I!' 
· 
5659 Southfield Drive, Flowery Branch, GA 30542 
i T clephone: 770-965-0006 
f-::S-tu-d7 y-· -::I_n_v-es-t7ig-a""t_o_r.L...J..__ 
----1 
-D-1-.. -=R_o_o_p_a"'li-K"'.-s"'o_m_a_n'"'i,-=M-=D_P_l_Ja_n_n_a_c __ o_lo_g_y _______ -1 
Principal 
11~~ 
,. 
Clinical Phannacology Department, 
1 
Investigator 
, 
ClinSync Clinical Research Pvt. Lt~., 
.J 
-CMP-SPI-001: Version 02; Date: 07 Aug 2018 
Page 16 of83 


I 
Protocol for Drug-Drug !nlcraction Study l)f Spironolactone and Digoxin (Fa;;Jing 
Condition) 
I 
I 
i 
Confidential 
--~·· f#-4=T:J~Hayathnau;;;:I:Jyd;::rabad~-· ····-----· 
-·----,~ 
1 
1 
.... _ 
[ i Tclangana- 501505, India. 
I 
I 
~--
J I Phone No.: +91-40-2420300112/3 
J' 
j /Fax No.: +91-40-24203000 
--+1-+/ Email ID: roopali.somani@clinsynccro.co:n . 
__ _ 
j / Dr. Sagar Chandra S Bhuyar, MD General Medicine, 
1 
1 Sub Investigator 
I 
Clinical 
. Investigator (s) 
1 I DNB (cardiology) 
j 
) 
ClinSync Clinical Research Pvt. Ltd., 
I 
I I 
#4-1-1, Hayathnagar, Hyderabad, 
1
./ 
: ! Telangana - 501505, India. 
Phone No.: +91-40-24203001/2/3 
Fax No.: +91-40-24203000 
1 • 
Dr. Chandra Prakash Vijaya Ram, MBBS 
I 
Clinical Phannacology Department, 
ClinSync Clinical Research Pvt. Ltd., 
I #4-1-1, Hayathnagar, Hyderabad, 
I Te!angana- 501505, India. 
Phone No.: +91-40-2420300112/3 
Fax No.: +91-40-24203000 
Email!D: cp.researchscientist@clinsynccro.com 
1
. 
Dr. Vani Malisetti, MD OBG 
I
I ~:::~c:1::~::::1o::~~:::::1:~., 
I #4-1-1, Hayathnagar, Hyderabad, 
I 
Telangana- 501505, India. 
I 
Phone No.: +91-40-24203001/213 
Fax No.: +9!-40-24203000 
Email ID: vani.malisetti@clinsynccro.com 
j : , Dr. Polepal!y Praveen Kumar, MBBS 
I I 
Clinical Pham1acology Department 
/ 
ClinSync Clinical Research Pvt. Ltd., 
-SPI-001; Version 02; Date: 07 Aug 2018 
_j 
Page 17 of83 


Protocol tOr Drug-Drug Interaction Study' 
1Jf Spironolactone nnJ Digoxin (Fasting 
Condition) 
Confidential 
..... , ··T#4·----------·----------· 
-
··-:--::c::-=---
1 
1 #4-l-1, Hayalhnagar, Hydcrabad, Tclangana - 501505, 
j · lndw. 
Phone No.: +9!-40- 2420300!1213 
i 
' Fax No.: +91-40-24203000 
/ _______________ L_I Email ID: p~lepally.praveenkumar@ clinsynccro.com 
j : I 
Mr. Clmag Khatn, M. Sc, 
. 
1 ClinSync Clinical Research Pvt. Ltd., 
Bioanalytical 
1 Investigator 
I 
Phannacokinetic 
, Investigator 
'#4-1-1, Hayathnagar, Hyderabad, 
Telangana- 501505, India. 
Phone No.: +91-40-24203001/2/3; Ext: 400 
Fax No.: +91-40-24203000 
Email ID: chirag.khatri@clinsynccro.com 
: 1 Dr. Jaganmohan S, M.Phann, Ph. D, PDF 
PK, BS and MW Department, 
ClinS ync Clinical Research Pvt. Ltd., 
, #4-1-1, Hayatlmagar, Hyderabad, 
I 
Telangana - 501505, India. 
Phone No.: +91-40-2420300 112/3; Ext: 604 
Fax No.: +91-40-24203000 
EmailiD: jaganmohan.somagoni@clinsynccro.com 
Statistical 
Investigator 
: , Mr. Tushar Shinde, M.Sc 
I 
I 
BS Department, 
ClinSync Clinical Research Pvt. Ltd., 
#4-1-1, Hayathnagar, H yderabad, 
Telangana - 501505, India. 
Phone No.: +91 -40-2420300112/3; Ext: 604 
' 
1 Fax No.: +9!-40-24203000 
I Email ID: tushar.shinde@clinsynccro.com 
' 
I List of Facilities involved in the Study 
Clinical 
Facility 
and 
Screening I 
' 
ClinSync Clinical Research Pvt. Ltd., 
Clinical Phannacology Department, 
-SPI-001; Version 02; Date: 07 Aug 2018 
Page 18 of83 


Protocol for Drug-Drug Interaction Study of Splmtlnbl:tone and D1goxin (Fasting 
C'omhtion) 
po;,·;;;~---- --·····) 
]#4:]'~]~-H;,yathnagar, Hyderabad, 
/ 
,. I T elangana - 501505, fndia. 
I 
1 
I Phone no.: +91-40-24203001/2/3 
I 
JFax no.: +91-40-24203000 
rsioanalytical, I : 
1.' ClinSync Clit~ical Research Pvt.-.L-tcC'' 
/ Phannacokinetic I , #4-1-l, Hayathnagar, Hyderabad. 
' ;r::ility Statistical 
1
, 
;~~a~:::a ~:~ ~:~~;:~~~'~0 I/213 
Fax no.: +91-40-24203000 
, Clinical Laboratory ' : I Medcis Pathlabs India Pvt. Ltd. 
I 
Plot 16 & 17, S wathi plaza, 
. 
Bhavam Enclave, Anand Nagar, 
/ 
New Bowenpally, Secunderabad-500 011. 
/ 
I Phone: 07702 29 29 29 
Email: info@medcislabs.com 
X-Ray Facility 
SUNRISE HOSPITALS 
H. #: 4-9-321, Plot# 4 & 7, 
Hayatlmagar, R.R. Dist, Hyderabad-501505. 
Phone no.: 9700009432 
And/or 
ClinSync Clinical Research Pvt. Ltd., 
Clinical Pharmacology Department, 
#4-1-1, Hayathnagar, Hyderabad, 
Telangana - 501505, India. 
G.J. Multiclave (India) Pvt. Ltd., 
Confidential 
I 
I 
I 
1 
BioMedical Waste 
1
. : 
I Management and 
1 Disposal 
7-1-47/liA, D.K.Road, Ameerpet, Hyderabad-500 016, 
J Telangana, India. 
'Phone No.: 040 23756925,30907999 
L---------~-L_______________________________j 
f VASAVIINSTiTUTfO 
I 
ETHIC~ C"'M 
, 
'· f,[oto'tot~J:l'~-C 1P-SPI-00l; Version 02; Date: 07 Aug 2018 
Ll L'ROVED 
Page 19 of83 


Protocol 
t~1r Drug-Drug Interaction Study of Spironolactone and Digox1n (Fasting 
Cond1tion) 
Conlidcnli<11 
2 
... ·····•····••·•··•• ················-··-·---
1 Emerg;;;;-~;;·---T-f suNR.Is.f:'ilosP!fA.r::s---·--········ ····· 
/Services 
1 f H. II: 4-9-321, Plot# 4 & 7, Hayathnagar, R.R. Dist, 
I 
I, 
I ~~ Hyderabad-501505. 
1 
I Phone no.: 9700009432 
/IEC 
----·] : Vasavi Institutional ethics committee, 
j 
J 
1 Vasavi Medical Research Center 
I 
I #6-1-91, Lakdikapul, Khairatabad, 
I, / 
Hyderabad, Telangana 500004 
i Phone no.: 040-65131333 
I I 
BACKGROUND INFORJ\IA TION 
I 
Patients frequently use more than one medication at a time. Unanticipated, 
unrecognized, or mismanaged DD!s are an important cause of morbidity and 
mortality associated with presctiption drug use and have occasionally caused the 
withdrawal of approved drugs from the market. In some instances, understanding 
how to safely manage a DD! may allow the FDA to approve a drug that would 
otherwise have an unacceptable level of tisk. 
The goal of a DDI study with pharmacokinetic endpoints is to inform clinical 
management strategies by detennining whether there is a clinically significant 
increase or decrease in exposure to the substrate in the presence of the perpetrator. 
Clinical DDI studies compare substrate concentrations in the absence and 
presence of a perpetrator drug in vivo. The tenus substrate is used to refer to the 
drug whose exposure may or may not be changed by a perpetrator drug. The tenn 
perpetrator refers to the drug that causes an effect on the substrate drug by 
inhibiting or inducing enz}ones or transp01ters. 
T,>pes of DDI Studies 
J. 
Prospective Studies and Retrospective Evaluations 
2. 
DDI Studies with Index Perpetrators and Index Substrates 
3. 
DDI Studies with Expected Concomitant Drugs 
Index substrates and perpetrators are not chosen based on their use in the 
investigational drug's target population, but rather because of their well-defined 
-=~~===.m~ction effects that provide information about the 
W·SI\Vi l!'lSTITUTIO 
l 
DOl potential of the 
l· 0 ' 
, .-,:,niV,nMT-rfTT;,.E;p:~"--f---------------------
- 'pi·otocol 
1o C-CMP·SP!-001. VersiOn 02; Date: 07 Aug 2018 
Page 20 of83 
I I'' 
~ '1'./t:: , I 
t!:~ 
4 " K:: , , 


Prntocol for Drug-Drug lntcraction Study cJf Spironolactone and Digoxm {Fas!ing 
Condition) 
ConJ!clential 
investigational drug. Thcrcf(H-c, the results ti·0111 DDI studrcs with rndex 
perpetrators or substrates arc used to either extrapolate findings to concomitant 
medications sharing the same DOl proper1ies or to help design DOl studies with 
commonly used concomitant medications in the investigational drug's target 
population. In contrast to DDl studies with index dnrgs, results ti·om a 
concomitant-use study with a non-index drug can be difficult to extrapolate to 
other drugs. 
The relevant concomitant medications for study include those used to treat the 
same condition for which the investigational drug is being studied or those used to 
treat common co-morbidities in the patient population. 
The purpose of most DDJ studies is to determine the ratio of a measure of 
substrate drug exposure (e.g., AUC ratio) in the presence and absence of a 
perpetrator drug. 
Pharmacola'netics 
Typical pharmacokinetic endpoints for DDI studies include changes in drug 
exposure parameters such as Cmo.x and AUCo.n. Phannacokinetic sampling times 
should be sufficient to characterize the C,,.,, and AUCo.72• The sampling times for 
single-dose studies should be planned so that the mean difference between the 
Cmax and AUCo.n is less than 20 percent. Phannacokinetic results of DDI study 
will be reported as the geometric mean ratio of the observed pharmacokinetic 
exposure measures with and without the perpetrator drug and include the 
associated 90 percent confidence interval. Observed variability of the interaction 
will also be reported. 
Interpretation ojDDI Study Results 
The results of a DOl study are interpreted based on the no-effect boundaries for 
the substrate drug. No-effect boundaries represent the interval within which a 
change in a systemic exposure measure is considered not significant enough to 
watTant clinical action (e.g., dose or schedule adjustment, or additional therapeutic 
monitoring). When the 90 percent confidence intervals for systemic exposure 
ratios fall entirely within the equivalence range of 80 to 125 percent, the study 
r\[';;C;;;-;;-;""';:-;c~o~n;;c;;lu;:;de:;:s:;.·;:;that there is no clinically significant DOl. 
, VASAVI!NSTITUTIONAL 
l 
ET 
1CS COMMITT!iF 
I A~ {..gtocol'No.: c=C P-SPJ-001; Version 02; Date: 07 Aug 2018 
lt'::Y~s-'" ROVED 
Page 21 of83 


Protocol f(.)r Drug-Drug lntcr<1L'tiot1 Study nJ 
Sp!nl!1t)lactone and Digoxin (Fasting 
Condition) 
Confidential 
2.1 
Spironoladonc (CaroSpir1'') 
2.1.1 
Description of Investigational Product 
CaroSpir"' (Spironolactone) Oral Suspension contains 25 mg of the aldosterone 
antagonist spironolactone, 17-hydroxy-7n-mercapto-3-oxo-l7a-pregn-4-ene-2l-
carboxylic acid y-lactone acetate per 5 mL, which has the following structural 
fommla: 
0 
2.1.2 
Pharmacology 
Mechanism of Action 
Spironolactone and its active metabolites are specific pham1acologic antagonists 
of aldosterone, acting primarily through competitive binding of receptors at the 
aldosterone-dependent sodium-potassium exchange site in the distal convoluted 
renal tubule. Spironolactone causes increased amounts of sodium and water to be 
excreted, while potassium is retained. Spironolactone acts both as a diuretic and as 
an antihypertensive drug by this mechanism. It may be given alone or with other 
diuretic agents that act more proximally in the renal tubule. 
2.1.3 
Pharmacokinetics 
For an equivalent dose, Spironolactone Oral Suspension results in 15 to 37% 
higher sentm concentration compared to Aldactone tablets. lnfom1ation about the 
dose proportionality of spironolactone tablets is limited and, based on the results 
of stndies comparing the suspension to tablets, doses of suspension higher than 
100 mg might result in spironolactone concentrations that could be higher than 
expected. 
Absorption 
The peak plasma concentration (Cm,) of spironolactone is reached 0.5 to 1.5 
hours atler dosing in healthy volunteers; for the active metabolite canrcnone, the 
· ·s reached around 2.5 to 5 hours after dosing. 
f'"'\Jjr-~·t\V! ir'JST 
I' F!HCS COpHJ'iflCrn.!No: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
tAP' 1ROVED 
Page 22 of83 


Protocol 1t)r Drug-Drug lnteradion Study of Spironolactone and Digoxin (Fast1ng 
Conditit)n) 
Contidcnttal 
Ljfect offood. A high fat and !ugh caloric meal (57% of the ~I 000 kcal of the 
meal was fi·om fat) increased the bioavailability of spironolactone (as measured by 
AUC) by approximately 90%. Patients should establish a routine pattem lor taking 
CaroSpir with regard to meals. 
Distribution 
Spironolactone and its metabolites arc more than 90% bound to plasma proteins. 
Metabolism 
Spironolactone is rapidly and extensively metabolized. Metabolites can be divided 
into two main categories: those in which sultur of the parent molecule is removed 
(e.g., canrenone) and those in which the sulfur is retained (e.g., TMS and HTMS). 
In humans, the potencies ofTMS and 7-a-thiospirolactone in reversing the effects 
of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte 
composition were approximately a third relative to spironolactone. However, 
since the serum concentrations of these steroids were not determined, their 
incomplete absorption and/or first-pass metabolism could not be ruled out as a 
reason for their reduced in vivo activities. 
Elimination 
The half-life of spironolactone is approximately 1- 2 hour, and the half-lite of 
canrenone, 
7-a-(thiomethyl) 
spirolactone 
(TMS), 
and 
6-13-hydroxy-7-a-
(thiomethyl) spiro lactone (HTMS) ranged from 10 to 35 hours. 
Pharmacokinetic Parameters: 
I 
Parameters 
Spironolactone 
Canrenone 
__j 
----
--
Tmax (hours) 
0.5- 1.5 
2.5-5 
___j 
Mean tem1inal T~;: (hours) 
I - 2 
10-35 
2.1.4 
Drug Interactions 
Drugs and Supplements Increasing Serum Potassium 
Concomitant administration of Spironolactone Oral Suspension with potassium 
supplementation or drugs that can increase potassium may lead to severe 
hyperkalemia. In general, discontinue potassium supplementation in heart failure 
patients who start Spironolactone Oral Suspension. Check serum potassium levels 
f\IASA\il ~'·!STITUTIO 
IAc;,~!pf~8Q&lMJi"{{EE:-
P-SPI-001; Version 02; Date: 07 Aug 2018 
~·· .£'\, VED 
Page 23 of83 
j 


Pro!tk·ol t(1r Drug-Drug Interaction Study of SpironoLlctonc and D1goxm (h.htll1g 
Condition) 
ConJidcntial 
when ACE inhibitor or ARB therapy is altered 
111 
patients receiving 
Spironolactone Oral Suspension. 
Examples of drugs that can increase potassium include: 
• 
ACE inhibitors 
• 
angiotensin receptor blockers 
• 
aldosterone blockers 
• 
non-steroidal anti-inflammatory drugs (NSA!Ds) 
• 
heparin and low molecular weight heparin 
• 
trimethoprim 
Lithium 
Like other diuretics, Spironolactone Oral Suspension reduces the renal clearance 
of lithium, thus increasing the risk of lithium toxicity. Monitor lithium levels 
periodically when Spironolactone Oral Suspension is co-administered. 
Nonsleroidal Anti-Jnjlamrnalory Drugs (NSAIDs) 
In some patients, the administration of an NSAID can reduce the diuretic, 
natriuretic, and antihypertensive effect of loop, potassium-sparing, and thiazide 
diuretics. Therefore, when Spironolactone Oral Suspension and NSAJDs are used 
concomitantly, monitor closely to determine if the desired effect of the diuretic is 
obtained. 
Digoxin 
Spironolactone and its metabolites interfere with radio immunoassays for digoxin 
and increase the apparent exposure to digoxin. It is unknown to what extent, if 
any, spironolactone may increase actual digoxin exposure. In patients taking 
concomitant digoxin, use an assay that does not interact with spironolactone. 
Cholestyramine 
Hyperkalemic metabolic acidosis has been repot1ed 
in patients gtven 
spironolactone concurrently with cholestyramine. 
Acetvlsalicylic Acid 
Acetylsalicylic acid may reduce the efficacy of spironolactone. Therefore, when 
Spironolactone Oral Suspension and acetylsalicylic acid are used concomitantly, 
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PnJtocol for Drug-Drug lntcr;Ktion Study of Spironolactone and D1go:xin (Fasting 
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Confidential 
dose and the patient should be observed closely to dctcnninc if the desired effect 
is obtained. 
2.1.5 
Indications 
Heart Failure: Spironolactone Oral Suspension is indicated f(1r treatment of 
NYHA Class Ill-lV hem1 failure and reduced ejection traction to increase 
survival, manage edema, and to reduce the need for hospitalization for heart 
failure. 
Spironolactone Oral Suspension is usually administered in conjunction with other 
heart failure therapies. 
Hypertension: Spironolactone Oral Suspension is indicated as an add-on therapy 
for the treatment of hype11ension, to lower blood pressure in adult patients who 
are not adequately controlled on other agents. Lowering blood pressure reduces 
the risk of fatal and nonfatal cardiovascular events, primarily strokes and 
myocardial in£1rctions. These benefits have been seen in controlled trials of 
antihypertensive drugs from a wide variety of phannacologic classes. 
Edema caused by Cirrhosis: Spironolactone Oral Suspension is indicated for the 
management of edema in adult cirrhotic patients when edema is not responsive to 
fluid and sodium restriction. 
2.1.6 Adverse Effects 
Clinical Trials Experience 
The following clinically significant adverse reactions are described in Warnings 
m1d precautions: 
• 
Hyperkalemia 
• 
Hypotension and Worsening Renal Function 
• 
Electrolyte and Metabolic Abnonnalities 
• 
Gynecomastia 
• 
Impaired neurological function! coma in patients with hepatic impainnent, 
cirrhosis and ascites 
The following adverse reactions associated with the use of spironolactone were 
identified in clinical trials or post marketing reports. Because these reactions were 
re orted vo!untmily from a population of uncertain size, it is not alwavs possible 
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Protocol f()r Drug-Drug Interaction Study of Spironolactone and Digo.xin (Fasting 
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Contidcntwl 
to estimate their ti-cquency, reliably, or lo establish a causal relatiOnship to drug 
exposure. 
Digestin.): Gastric bleeding~ ulceration, gastritis, diarrhea and cramping, nausea, 
vm11iting. 
Reproductive: Gynecomastia, decreased libido, inability to achieve or maintain 
erection, itwgular menses or amenorrhea, postmenopausal bleeding, breast and 
nipple pain. 
Hema!Oiogic: Leukopenia (including at,>ranulocytosis), thrombocytopenia. 
Hypersensitivity: Fever, urticatia. maculopapular or erythematous cutaneous 
eruptions, anaphylactic reactions, vasculitis. 
Metabolism: Hyperkalemia, electrolyte disturbances, hyponatremia, hypovolemia. 
Musculoskeletal: Leg cramps. 
Nervous system /psychiatric: Lethargy, mental confitsion, ataxia, dizziness, 
headache, drowsiness. 
Liver I biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with 
one reported fatality, have been reported with spironolactone administration. 
Renal: Renal dysfunction (including renal failure). 
Skin; Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug 
rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritis, 
chloasma. 
2.1.7 
Dosage & Administration, Contraindications and Warnings 
Spironolactone Oral Suspension is not therapeutically equivalent to Aldactone. In 
patients requiring a dose greater than I 00 mg, use another fonnulation. Doses of 
the suspension greater than l 00 mg may result in spironolactone concentrations 
higher than expected. 
Spironolactone Oral Suspension can be taken with or withottl food, but should be 
taken consistently with respect to food. 
Contraindications 
Spironolactone Oral Suspension is contraindicated for patients with the following 
conditions: 
• 
Hyperkalemia 
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Protucol l(n Drug-Drug lntcrac!Ion Stud_y tlf Spironolactone and Digoxin (Fasting 
Condition) 
• 
Addison's disease 
• 
Concomitant usc of cplcrcnone 
\Varning and precautions 
N1perka/emia 
Confidential 
Spironolactone Oral Suspension can cause hyperkalemia. This risk is increased by 
impaired renal function or concomitant potassium supplementation, potassium-
containing salt substitutes or drugs that increase potassium, such as angiotensin 
conve11ing enzyme inhibitors and angiotensin receptor blockers. 
Closer monitoring may be needed when Spironolactone Oral Suspension is given 
with other drugs that cause hyperkalemia or in patients with impaired renal 
function. 
lf hyperkalemia occurs, decrease the dose or discontinue Spironolactone Oral 
Suspension and treat hyperkalemia. 
Nvpotension and Worsening Renal Function 
Excessive diuresis may cause symptomatic dehydration, hypotension and 
worsening renal function, particularly in salt-depleted patients or those taking 
angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. 
Worsening of renal function can also occur with concomitant use of nephrotoxic 
drugs (e.g., aminoglycosides, cisplatin, and NSA!Ds). Monitor volume status and 
renal function periodically. 
ElectroZvte and Metabolic Abnormaliries 
In addition to causing hyperkalemia, Spironolactone Oral Suspension can cause 
hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis, and 
hyperglycemia. Asymptomatic hyperuricemia can occur and rarely gout is 
precipitated. Monitor serum electrolytes, uric acid and blood glucose periodically. 
Gynecomastia 
Spironolactone Oral Suspension can cause gynecomastia. In RALES, patients 
with heart failnre treated with a mean dose of 26 mg of spironolactone once daily, 
about 9% of the male subjects developed gynecomastia. The risk of gynecomastia 
increases in a dose-dependent manner with an onset that varies widely from 1-2 
'"~"·······~·~-·==lll'~i.lf,tQ.over a year. Gynecomastia is usually reversible. 
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Protocol for Drug-Drug lntcractlon SlLHh of Spironolactone and Digoxin (Fasting 
Condition) 
2.2 
Digoxin (LANOXIN'') 
2.2.1 
Description of Investigational Product 
Digoxin is the cardiac (or digitalis) glycoside, having eflects on the myocardium. 
This dmg is found in a number of plants. Digoxin is extracted !rom the leaves of 
Digilalis lana/a. The tenn "digitalis" is used to designate the whole group of 
glycosides. The g!ycosidcs are composed of 2 portions: a sugar and a cardenolidc 
(hence "glycosides"). 
Digoxin is described chemically as (3P,5P.l2/3)-3-[(0-2,6-dideoxy-f3-D-ribo-
hexopyranosyl-( 1->4 )-0-2.6-dideoxy-13-D-ribo-hexopyranosyl-( ]--.4 )-2,6-
dideoxy-/3-D-ribo-hexopyranosyl)oxy ]-12, 14-dihydroxy-card-20(22)-enolide. 
Its 
molecular fonnula is c,,H6,o,,, its molecular weight is 780.95, and its structural 
fonnula is: 
0 
H .•• 
OH 
C) 
r OH 
H 
3 
H 
2.2.2 
Pharmacology 
Mechanism of Action 
Digoxin inhibits sodium-potassium ATPase, an enzyme that regulates the quantity 
of sodium and potassium inside cells. Inhibition of the enzyme leads to an 
increase in the intracellular concentration of sodium and thus (by stimulation of 
sodium-calcium exchange) an increase in the intracellular concentration of 
calcium. The beneficial effects of digoxin result from direct actions on cardiac 
muscle, as well as indirect actions on the cardiovascular system mediated by 
~---·~·"= 
effects on the autonomic nervous system. The autonomic effects include: (I) a 
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Condition) 
Confidential 
vagomimetic action, which is responsible tor the effects of digoxin on the 
sinoatrial and atrioventricular (A V) nodes; and (2) baroreceptor sensitization. 
which results in increased afferent inhibitory activity and reduced activity of the 
sympathetic nervous system and renin-angiotensin system for any given increment 
in mean arterial pressure. 
2.2.3 
Pharmacokinetics 
Absorption 
Following oral administration, peak serum concentrations of digoxin occur at l to 
3 hours. Absorption of digoxin from Digoxin Tablets has been demonstrated to be 
60% to 80% complete compared to an identical intravenous dose of digoxin 
(absolute bioavailability). When Digoxin Tablets are taken after meals, the rate of 
absorption is slowed, but the total amount of digoxin absorbed is usually 
unchanged. When taken with meals high in bran fiber, however, the amount 
absorbed from an oral dose may be reduced. 
Distribution 
Following drug administration, a 6- to 8-hour tissue distribution phase is 
observed. This is followed by a much more gradual decline in the serum 
concentration of the drug, which is dependent on the elimination of digoxin from 
the body. The peak height and slope of the early portion (absorption/distribution 
phases) of the serum concentration-time curve are dependent upon the route of 
administration and the absorption characteristics of the formulation. 
Digoxin is concentrated in tissues and therefore has a large apparent volume of 
distribution. Digoxin crosses both the blood-brain barrier and the placenta. 
Metabolism 
Only a small percentage (I 6%) of a dose of digoxin is metabolized. The end 
metabolites, which include 3 J3-digoxigenin, 3-keto-digoxigenin, and their 
glucuronide and sulfate conjugates, are polar in nature and are postulated to be 
fonned via hydrolysis, oxidation, and conjugation. The metabolism of digoxin is 
not dependent upon the cytochrome P-450 system, and digoxin is not known to 
induce or inhibit the cytochrome P-450 system. 
Elimination 
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Protocol fc1r Drug-Drug lnkraction Study of Spironulacton~ and Digoxin (Fa;-;ting 
Cnndition) 
Conlidcntial 
Elimination of digoxin follows first-order kinetics (that is, the quantity ,,f digoxin 
eliminated at any time is propot1ional to the total body content). Following 
intravenous administration to healthy volunteers, 50% to 70% of a digoxin dose is 
excreted unchanged in the urine. Renal excretion of digoxin is prop011ional to 
glomerular filtration rate and is largely independent of urine tlow. In healthy 
volunteers with normal renal function, digoxin has a half-lite of I .5 to 2.0 days. 
The half-life in an uric patients is prolonged to 3.5 to 5 days. 
Pharmacokineric Parameters: 
Parameters 
I 
Digoxin 
Tma., (hours) 
I - 3 
L Mean tenninal Tu (days) 
J 
1.5-2.0 
2.2.4 
Drug Interactions 
Potassium-depleting diuretics are a major contributing factor to digitalis toxicity. 
Calcium, particularly if administered rapidly by the intravenous route, may 
produce serious arrhythmias in digitalized patients. Quinidine, vcrapamil, 
amiodarone, 
propafenone, 
indomethacin, 
itraconazole, 
alprazolam, 
and 
spironolactone raise the serum digoxin concentration due to a reduction in 
clearance and/or in volume of distribution of the drug, with the implication that 
digitalis intoxication may result. Erythromycin and clarithromycin (and possibly 
other macrolide antibiotics) and tetracycline may increase digoxin absotption in 
patients who inactivate digoxin by bacterial metabolism in the lower intestine, so 
that digitalis intoxication may result. Propantheline and diphenoxylate, by 
decreasing gut motility, may increase digoxin absotption Antacids, kaolin-pectin, 
sulfasalazine, 
neomycm, 
cholestyramine, 
certain 
anticancer 
drugs, 
and 
metoclopramide may interfere with intestinal digoxin absotption, resulting in 
unexpectedly low serum concentrations. Rifampin may decrease serum digoxin 
concentration, especially in patients with renal dysfunction, by increasing the non-
renal clearance of digoxin. There have been inconsistent reports regarding the 
effects of other drugs (e.g., quinine, penicillamine) on serum digoxin 
concentration. Thyroid administration to a digitalized, hypothyroid patient may 
, ...... _._ 
increase the dose requirement of digoxin. Concomitant use of digoxin and 
: V/l,Sf\\/1 iti:~TITUTiONAL 
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at omimetics increases the risk of cardiac arrhythmias. Succinylcholine may 
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Protocol t()r Drug-Drug lnkraction StuJy of SpirLH10lactonc and Digoxin (Fasting 
Condition) 
Coniid~ntwl 
cause a sudden extrusion of potassium frmn muscle cells, and may thereby cause 
an·hythmias in digitalized patients. Although calcium channel blockers and 
digoxin may be useful in combination to control atrial tibrillation, their additive 
effects on A V node conduction can result in advanced or complete heart block. 
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and 
decrease hemi rate. Concomitant use can increase the risk of bradycardia. Digoxin 
concentrations are increased by about 15% when digoxin and carvedilol are 
administered concomitantly. Therefore, increased monitoring of digoxin is 
recommended when initiating, adjusting, or discontinuing carvedilol. 
Due to the considerable variability of these interactions, the dosage of digoxin 
should be individualized when patients receive these medications concurrently. 
Furthennore, caution should be exercised when combining digoxin with any drug 
that may cause a significant deterioration in renal function, since a decline in 
glomerular filtration or tubular secretion may impair the excretion of digoxin. 
2.2.5 
Indications 
Heart Failure 
Digoxin Tablet is indicated for the treatment of mild to moderate heart failure. 
Digoxin Tablet increases left ventricular ejection fraction and improves heart 
failure symptoms as evidenced by exercise capacity and heart failure-related 
hospitalizations and emergency care, while having no effect on mortality. Where 
possible, Digoxin Tablets should be used with a diuretic and an angiotensin-
converting enzyme inhibitor, but an optimal order for starting these 3 drugs cannot 
be specified 
Atrial Fibrillation 
Digoxin Tablets is indicated for the control of ventricular response rate in patients 
with chronic atrial fibrillation. 
2.2.6 
Adverse Effects 
Clinical Trials Experience 
In general, the adverse reactions of digoxin are dose-dependent m1d occur at doses 
higher thm1 those needed to achieve a therapeutic effect. Hence, adverse reactions 
are less conm1on when digoxin is used within the recommended dose range or 
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Protocol fiJr Drug-Drug Inte-raction Study of Spironolactone and Digoxin (Fasting 
Condition) 
Confidential 
therapeutic serum concentration range and when there is careful attention to 
concurrent medications and conditions. 
Because some patients may be pmiicularly susceptible to side effects with 
digoxin, the dosage of the dmg should always be selected carefully and adjusted 
as the clinical condition of the patient warrants. In the past, when high doses of 
digoxin were used and little attention was paid to clinical status or concurrent 
medications, adverse reactions to digoxin were more frequent and severe. 
Cardiac 
Therapeutic doses of digoxin may cause heart block in patients with pre-existing 
sinoatrial or A V conduction disorders; heart block can be avoided by adjusting the 
dose of digoxin. Prophylactic use of a cardiac pacemaker may be considered ifthe 
risk of heart block is considered unacceptable. High doses of digoxin may produce 
a variety of rhythm disturbances, such as 
first-dc!,'fee, 
second-degree 
(Wenckebach), or third-degree heart block (including asystole); atrial tachycardia 
with block; A V dissociation; accelerated junctional (nodal) rhythm; unifocal or 
multiform ventricular premature contractions (especially bigeminy or trigeminy); 
ventricular tachycardia; and ventricular fibrillation. 
Gastrointestinal 
Digoxin may cause anorexia, nausea, vomiting, and diarrhea. Rarely, the use of 
digoxin has been associated with abdominal pain, intestinal ischemia and 
hemorrhagic necrosis of the intestines. 
CNS 
Digoxin can produce visual disturba11ces (blurred or yellow vision), headache, 
weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, 
depression, delirium, and hallucination). 
Other 
Gynecomastia has been occasionally observed following the prolonged use of 
digoxin. Thrombocytopenia and maculopapular rash and other skin reactions have 
been rarely observed. 
Adverse experiences listed below for patients treated with Digoxin Tablets or 
r
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Condition) 
Contidcntial 
Patients ln these trials \VCre also receiving diuretics with or without angiotensin-
converting enzyme inhibitors. These patients had been stable on digoxin, and were 
randomized to digoxin or placebo. 
Care/we: Palpitation, Ventricular extra systole, Tachycardia, Heart arrest. 
cTasrroinlestinal: Anorexia, Nausea, Vomiting, Diarrhea, Abdominal pain 
CNS: Headache, Dizziness, Mental disturbances. 
01/zer: Rash, Death. 
2.2.7 
Dosage & Administration, Contraindications and Warnings 
Dosage & Administration 
Recommended dosages of digoxin may require considerable modification because 
of individual sensitivity of the patient to the drug, the presence of associated 
conditions, or the use of concurrent medications. In selecting a dose of digoxin, 
the following factors must be considered: 
• 
The body weight of the patient. Doses should he calculated based upon lean 
(i.e., ideal) body weight. 
• 
The patient's renal function, preferably evaluated on the basis of estimated 
creatinine clearance. 
• 
The patient's age. Infants and children require different doses of digoxin than 
adults. Also, advanced age may be indicative of diminished renal function 
even in patients with nmmal serum creatinine concentration (i.e., below 
1.5 mg/dL). 
• 
Concomitant disease states, concutTent medications, or other factors likely to 
alter the phannacokinetic or pharmacodynamic profile of digoxin. 
Contraindications 
Digitalis glycosides are contraindicated in patients with ventricular fibrillation or 
in patients with a known hypersensitivity to digoxin. A hypersensitivity reaction 
to other digitalis preparations usually constitutes a contraindication to digoxin. 
Warning and precautions 
Sinus Node Disease and AV Block 
Because digoxin slows sinoatrial and A V conduction, the dmg commonly 
interval. The drug may cause severe sinus bradycardia or 
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Pt\Jtocol for Drug-Drug Interaction Stud.Y or Spnonn!actonc <lnd Digoxin (Fasting, 
Conchtion) 
Confidential 
- --------------- --------
sinoatrial block in patients with pre-existing sinus node disease and may cause 
advanced or complete heart block in patients with pre-existing incomplete A V 
block. In such patients, consideration should be given to the insertion of a 
pacemaker before treatment with digoxin. 
Access01y A V Pathway (WotfrParkinson-/VIzitc Sv11drome) 
After intravenous digoxin therapy, some patients with paroxysmal atrial 
fibrillation or flutter and a coexisting accessory A V pathway have developed 
increased antegrade conduction across the accessory pathway bypassing the A V 
node, leading to a very rapid ventricular response or ventricular fibrillation. 
Unless conduction down the accessory pathway has been blocked (either 
pharmacologically or by surgery), digoxin should not be used in such patients. 
The treatment of paroxysmal supraventricular tachycardia in such patients is 
usually direct-current cardioversion. 
Usc in Patients Hith Preserved Left Ventricular Systolic Function 
Patients with certain disorders involving heart failure associated with preserved 
left ventricular ejection fraction may be particularly susceptible to toxicity of the 
drug. Such disorders include restrictive cardiomyopathy, constrictive pericarditis, 
amyloid heart disease, and acute cor pulmonale. Patients with idiopathic 
hypertrophic subaortic stenosis may have worsening of the outflow obstruction 
due to the inotropic effects of digoxin. Digoxin should generally be avoided in 
these patients, although it has been used for ventricular rate control in the 
subgroup of patients with atrial tibrillation. 
Usc in Patients with Impaired Renal Function 
Digoxin is primarily excreted by the kidneys; therefore, patients with impaired 
renal function require smaller than usual maintenance doses of digoxin. Because 
of the prolonged elimination half-life, a longer period of time is required to 
achieve an initial or new steady-state serum concentration in patients with renal 
impainnent than in patients with nonnal renal function. If appropliate care is not 
taken to reduce the dose of digoxin, such patients are at high risk for toxicity, and 
toxic effects will last longer in such patients than in patients with nom1al renal 
·-----~ .. --.. 
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Prmocol for Drug-Drug Interaction Study of Spironolactone and Digoxin (Fasting 
Condit ion) 
Con Iiden! ial 
Usc in Pa!ienls 1rith Elec/roi)'/c Disorders 
In patients with hypokalemia or hypomagnesemia, toxicity may occur despite 
serum digoxin concentrations below 2.0 ng/mL, because potassium or magncsiun1 
depletion sensitizes the myocardium to digoxin. Theref(>re, it is desirable to 
maintain normal serum potassium and magnesium concentrations in patients being 
treated with digoxin. Deficiencies of these electrolytes may result from 
malnutrition, diarrhea, or prolonged vomiting, as well as the use of the following 
drugs or procedures: diuretics, amphotericin B, corticosteroids, antacids, dialysis, 
and mechanical suction of gastrointestinal secretions. 
Hypercalcemia from any cause predisposes the patient to digitalis toxicity. 
Calcium, particularly when administered rapidly by the intravenous route, may 
produce serious arrhythmias in digitalized patients. On the other hand, 
hypocalcemia can nullify the effects of digoxin in humans; thus, digoxin may be 
ineffective until serum calcium is restored to normal. These interactions are 
related to the fact that digoxin affects contractility and excitability of the heart in a 
manner similar to that of calcium. 
Use in Thyroid Disorders and Hypermetabolic States 
Hypothyroidism may reduce the requirements tor digoxin. Heart failure and/or 
atrial arrhythmias resulting from hypennetabolic or hyperdynamic states (e.g., 
hyperthyroidism, hypoxia, or arteriovenous shunt) are best treated by addressing 
the underlying condition. Atrial arrhythmias associated with hypennetabolic states 
are particularly resistant to digoxin treatment. Care must be taken to avoid toxicity 
if digoxin is used. 
Use in Palients with Acute Myocardial infarction 
Digoxin should be used with caution in patients with acute myocardial infarction. 
The use of inotropic drugs in some patients in this setting may result in 
undesirable increases in myocardial oxygen demand and ischemia. 
Use During Eleclrical Cardioversion 
It may be desirable to reduce the dose of digoxin for I to 2 days prior to electJical 
cardioversion of atrial fibrillation to avoid the induction of ventricular 
arrhythmias, but physicians must consider the consequences of increasing the 
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Protocol for Drug-Drug Interaction Study nf Spironolac1nnc and Digt.).Xin (Fasting 
Condition) 
Con tidcntial 
ventricular response if digoxin is withdrawn. If digitalis toxicity is suspected, 
elective cardiovcrsion should be delayed. If it is not prudent to delay 
cardioversion, the lowest possible energy level sil<luld be selected to avoid 
provoking ventricular anh)1hmias. 
Use in Patienls 1vilh ]..~yo carditis 
Digoxin can rarely precipitate vasoconstriction and theref(Jre should be avoided in 
patients with myocarditis. 
Use in Palients wilh BeriBeri Heart Disease 
Patients with beri beri heart disease may fail to respond adequately to digoxin if 
the underlying thiamine deficiency is not treated concomitantly. 
3 
STUDY OBJECTIVES AND PURPOSE 
3.1 
Objectives 
Primaty Objective: To charactetize the pham1acokinetic profiles of Digoxin 
(substrate drug) in the presence and absence of spironolactone (perpetrator) in 
healthy adult human subjects under fasting condition. 
Secondary objective: 
To assess whether there ts a drug-drug interaction with concomitant use of 
spironolactone. 
To measure renal clearance (CLR)/Percent Recovered and unchanged drug 
excreted in urine (fe)/ Amount Recovered for digoxin in the presence and absence 
of spironolactone (perpetrator) in healthy adult human subjects under fasting 
condition. 
To monitor safety of the subjects in dmg-drug interaction study. 
3.2 
Purpose 
CaroSpir"' is an oral suspension of spironolactone approved by FDA. Dllling the 
approval process, FDA recommended the sponsor, CMP Development LLC, 
USA, to conduct a drug-drug interaction of spironolactone oral suspension with 
Digoxin. Hence, this Drug-Drug Interaction Study of spironolactone oral 
suspension with Digoxin is planned with the stated objective to assess whether 
there is a drug-drug interaction resulting in increased digoxin levels with 
1itant use of spironolactone. 
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Protncol for Drug-Drug lntcrnctil1tl Study of Spnonolactonc and Digosin (Fastmg 
C'ond1tion) 
C'onlidcntial 
4 
STUDY DESIGN 
An open label, balanced, randomized. single-dose, two-treatment, two-sequence, 
two-period, crossover, drug-drug interaction study in healthy adult human subjects 
under fasting condition. 
Schematic Diagram of Study Design, Procedures and Stages are attached as 
Appendix I. 
4.1 
Number of Subjects 
28 healthy adult human subjects will be included in the study. Additionally, 04 
stand-by subjects will be included in order to dose 28 subjects in period I. 
4.2 
Randomization 
The order of receiving the treatment A and treatment B for each subject during the 
study will be determined randomly. According to the randomization schedule, 
subjects will receive the assigned tonnulation in each period, with the possible 
sequences 'AB' or 'BA' (where A = substrate and B = substrate & perpetrator). 
Equal allocation of subjects to each sequence will be ensured. The randomization 
will be balanced and the randomization schedule as well as the dispensing records 
will be kept in the drug store under controlled access. The study personnel 
involved in dispensing (pharmacist) and the Principal Investigator will be 
accountable for ensuring compliance to randomization schedule. Randomization 
schedule will be generated using SAS ~ software 9.3 or higher. 
4.3 
Blinding 
The study will be conducted as open label study. The study persmmel involved in 
the sample analysis will be kept blinded from the randomization schedule during 
entire study. 
4.4 
Housing and Washout period 
The subjects will be housed for at least 11.00 hours prior to drug administration 
on Day 1 until! the collection of96.00 hours blood sample on Day 10. There will 
be a washout period of at least 28 days between each consecutive treatment 
periods. 
5 
INVESTIGATIONAL PRODUCTS 
e··-··--·-·-··-- Treatment (A): LANOXJN" (digoxin) USP 250 meg (substrate drug) 
f VL.S/i_\, :· n\r:'---~r -; 
. 
fl!i''PMt't/MNii[l!=~-
P-SPl-00 I: Version 02; Date: 07 Aug 2018 
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fAp~p~:~OVED 


Protocol f(x Drug-Drug lntcract!OJJ Study l)f SpinHwlactonc and Digoxin (Fasting 
Condition) 
Confidential 
Treatment (B): LANOXlN' (digoxin) US!' 250 meg (substrate drug) 
~· 
Spironolactone Oral Suspension I 00 mg (perpetrator; Carospir" Oral Suspension 
20 mL of25 mg I 5 mL ofCMP Development LLC, USA.) 
5.1 
Receipt, Storage and Accountability of Investigational Products 
5.1.1 
Receipt of Investigational Products 
Sponsor should supply sut11cient quantity of investigational products, for 
administration to subjects as well as retention purpose. The perpetrator drug 
product (Spironolactone) will be supplied in PET bottles with child resistant caps 
and induction seal whereas substrate drug product (Digoxin) will be supplied in 
sealed packages and/or strips with appropriate label and ce1iificates of analysis. 
5.1.2 
Storage of Investigational Products 
After receipt of the investigational products, they will be transferred to the 
phannacy. The investigational products will be stored as per the storage 
conditions of investigational products in the phannacy. 
5.1.3 
Accountability of Investigational Products 
Accountability for the investigational products will be documented in the 
respective "Dispensing and accountability of IP's" record for the substrate and 
perpetrator dmg products as per applicable ClinSync SOP. 
5.1.4 
Dispensing 
The Pharmacist is responsible for dispensing and will dispense a quantity of the 
substrate and perpetrator drug products sufficient for dosing along with stand-by 
units for the pe1iod as per the randomization schedule and the remaining will be 
kept in their original containers as retention sample!:. As Carospir" is suspension, 
Phannacist will shake the bottle well (by means of inverting the bottle and 
shaking vigorously for at least 15 seconds) just before dispensing and the same 
will be documented. The dispensed doses will be transferred to the dmg-
dispensing sachets (tor tablet) and unit dose container (for suspension) and pre-
labeled (sample format) as shown below: 
I Project No: 
I 
Drug name: 
LSubject No: 
Period No: l 
I 
Treatment 
r~VASJ:Nf"'iN$T1TLJTIONAL 
1 ETHIC5-t~ew, m.-mrn:l:,....._,f-------------------------
ft,;,PP'R.tf\Yf:l) MP-SPI-001; Version 02; Date: 07 Aug 2018 
Page 38 of83 
E~p. Date: 


Protocol j()r Drug-Drug Interaction Stud) of Spironolactone ;md Digoxin (F<-1sting 
Condition) 
Confidential 
--- ----------- ------------------------------------
r~~,-,t-cl-,;~;;-1\-,o-: --------
Dosage Fonn: -----l 
/ Qty_ x strength: 
I 
j Storage conditions: 
1 
Dispensed by: ______________ _ 
AdministeredocbLy . .__· ~------~~ 
L-----"'(F:_.o_r.c__BA/BE Study Use Only) 
1 
5.1.5 
Handling of Unused Investigational Products 
The dispensed but un-dosed investigational product (tablets/substrate drug 
product) will be kept along with the remaining investigational product after 
completion of the project. Dispensed but un-dosed investigational product 
(suspension/perpetrator drug product) will be discarded as per in-house SOP. 
5.1.6 
Retention of Samples 
After completion of the study, remaining investigational products will be retained 
in the phanuacy as per applicable ClinSyuc SOP. 
6 
TREATMENT OF SUBJECTS 
6.1 
Treatments to be administered 
Treatment A 
Name of the Product 
LANOXIN@ (digoxin) USP 250 meg 
Dose 
250 meg 
Dosing Schedule 
i : One tablet as a single dose to each subject 
I 
Route/Mode of Administration 
Orally with 240 ± 2 mL of water 
Treatment Period 
Treatment B 
Name of the Product 
-----------j 
Single dose for I Day (day 6) as per 
randomization schedule 
I : LANOXIN01 (digoxin) USP-Z50 meg + j 
I
' . Spironol.actone Oral Suspension I 00 mg I 
j 
(CaroSpir"· Oral SuspensiOn 20 mL of 25 
/ 
mg/5mL) 
~-------------+-
Dose 
/ : . 250 meg of digoxin and 100 mg of 
~-·~'ASAV' if<STITUTW 
j ___ I spironolactone as 20 mL of 25 mg I 5 mL 
I ETHtCS ('::''"" 
! 1::~ 
lArPRCJ\!Et} ::-CMP-SP!-001; Version 02; Date: 07 Aug 2018 
Page 39 of83 


Protocol for Drug-Drug lntcraction Study of Spironolactone <lnd Digoxin {Fasting 
Condition) 
Confidenticl 
---;=:::=:::=:::=:::==::::::=·-----
~:1-----_ 
-~=-~:::: ·::::::::::::::::: -- -
--- -- - - - _---~ 
Dosing Schedule 
: / One tablet of digoxin and 20 mL of [ 
, 25mgl5m L CaroSpir oral suspension as a I 
1-------------------~-~~:gie_ dose_ to ca~h st~bjcct 
_______ J 
Route/Mode of Adnmnstratwn I .J Orally with about 240 x 2 mL of water 
/ 
Treatment Penod 
----~~ j Smgle 
dose 
for 
9 
Days 
-as -;:l 
I 
randomization schedule 
-~-J 
6.2 
Drug Administration 
Spironolactone Oral Suspension 100 mg (Perpetrator; Carospir~· Oral Suspension 
20 mL of 25 mg I 5 mL of CMP Development LLC, USA.) will be administered 
as a single dose from Day 1 to Day 5 and Day 7 to Day 9, to the subjects who will 
be randomized to treatment B as per randomization scheme. 
On Day 6, after ovemight fasting of at least I 0.00 hours, either of treatment (A) or 
treatment (B) will be administered orally to the subjects in sitting posture with 240 
± 2 mL of water, at ambient temperature as per the randomization scheme. After a 
wash out period of 28 days, the same procedure will be repeated during period-II. 
Subjects will be instructed not to chew or crush the tablet (for substrate drug) and 
swallow as a whole. 
Compliance for dosing will be assessed by a thorough check of the oral cavity 
immediately after dosing. 
A total of 240 ± 2 mL of water will be administered with investigational products. 
However, tor Treatment B, 120 mL of water with 20 mL of CaroSpir oral 
suspension and 120 mL of water with one tablet of Lanoxin. 
Instructions for suspension administration: 
I. CaroSpir oral suspension will be administered with a graduated syringe. 
2. 20 mL of 25 mg I 5 mL of Carospir"' Oral Suspension will be loaded in the 
syringes well in advance prior to dosing on the day of dosing. 
3. The suspension in the syringe will be directly administered to the subjects. 
4. The syringe will be rinsed with water (approximately I 0 mL fi·om 120 mL of 
dosing water) and will be administered to the subjects. This procedure will be 
followed till the syringe is free of the contents of the medication. Then the 
remaining quantity of water (from the 120 mL) will also be administered to 
Page 40 of83 


"'" 
" 
,· 
l ____ . ! ! i ·; ~) \'" i 
Protocol for 
Drug~Drug IntcrJction Study of Spironolactone and Digoxin (FastJ!lg 
Condition) 
Contidcnttal 
5. Drug administration will he can·ied out at the same dosing times f(Jr all dosing 
days (i.e. ti·01n Day OJ to Day 09). 
6. From Day I to 5 and Day 7 to 9, the Standard Breakfast will be served at 0.50 
hr (30 min) post dose. 
6.3 
Sampling Schedule 
Utine & Blood samples collection will be started after the completion of dosing 
on Day6. 
A total of II urine samples will be collected from each subject in each study 
period. 
Urine samples will be collected at intervals of (0.00-1.00), ( 1.00-2.00), (2.00-
4.00), ( 4.00-6.00), (6.00-8.00), (8.00-12.00), ( 12.00-I 6.00), (I 6.00-24.00), (24.00-
48.00), (48.00-72.00) and (72.00-96.00) hours post dose. 
Immediately out of the total volume of urine collected at each collection time 
interval, approximately I 0 mL (2 x 5 mL aliquots) of urine samples will be 
transferred into two pre-labeled containers for analysis. They will be stored at 
deep freezer maintained at -20°C or lower until dispatched from Clinical Unit to 
Bioanalytical Depariment for analysis. 
A total of25(1 x 5 mL) blood samples will be collected from each subject in each 
study period. Blood samples will be collected at pre-dose (0.00) and post dose at 
0.25, 0.50, 0.75, 1.00, 1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 
8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00, 60.00, 72.00 and 96.00 hours post 
dose in each period. 
Note: Blood samples up to 3 hours post dose will be collected at bed side. 
6.4 
Sampling Procedure 
Immediately out of the total volume of urine collected at each collection time 
interval, approximately !0 mL (2 x 5 mL aliquots) of urine samples will be 
transferred into two pre-labeled containers and will be stored at deep freezer 
maintained at ·20°C or lower until dispatched from Clinical Unit to Bioanal}1ical 
Depm1ment for analysis. The urine samples will be stored at -20°C or lower in the 
Bioanalytical facility until analysis. After collecting the mine samples from all the 
Page 41 of83 


Protocol f()J Drug-Drug lntcraci!On S1udy of Spironl)Jactone and Digoxin {Fasting 
Condition) 
Confidential 
subjects at each collection time interval, the total pooled volume will be noted 
dO\-VO. 
The urine samples will be transfcned to analytical site for analysis aiicr the 
completion of clinical phase. 
The pre and post-dose blood samples up to 24.00 hrs will be collected via an 
indwelling cannula place in an antecubital vein or one of the torearm vems. 
Heparin-lock technique (about 0.5 mL of heparinized saline [I ml of 5 !U/ml 
heparin in nom1al saline solution] will be injected into the cannula after each 
sample collection) will be used to prevent clotting of the blood in the indwelling 
cannula. Before each blood sample is drawn, 0.5 mL of blood will be discarded 
(except 36.00, 48.00, 60.00, 72.00 and 96.00 post dose samples and if the blood is 
being collected by a fresh vein-puncture) to prevent the heparin in the cannula 
from interfering with the analysis. 
At each time point, the blood samples will be collected in pre-labeled (Project 
No., Subject No, Period No, sampling time point and Sample !D) vacutainersK 
containing K2EDTA as anticoagulant. If for any reason the indwelling cannula is 
blocked or must be removed for practical reasons, the blood sample will be drawn 
by inserting a fresh cannula after removal of the blocked cannula or by direct 
venipw1cture, as decided by the investigator. If there are more than 2 draws that 
need to be done after the cannula is blocked, a fresh cmmula preferably will be 
inserted for that subject. 
The pre-dose blood smnple will be collected within 2 hours before dosing and the 
post-dose in-house samples will be collected with a window period of~ 2 minutes 
from the scheduled sampling time. 
During collection of blood smnple at each time point the mid-point of the minute 
will be considered to calculate the nearest minute, which will be recorded on the 
appropriate fonn. The deviations greater than mentioned in this protocol from the 
scheduled sampling time will be reported as protocol deviations. 
The actual time points will be taken into account for the Phmmacokinetic Analysis 
if any deviations occur for blood collection. 
IAPPR'lf\J~j) -CMP-SPI-001; Version 02; Date: 07 Aug2018 
~--~--_c;;.....::...=.;:::;,j 
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..........__~ 
Protocol for Drug-Drug Interaction Study of Spnonolact1Jnc and 
DlgJ)X\1'1 (Fasting 
Condition) 
Confidential 
Atter collecting the blood samples trom all the subjects at each sampling time 
point, samples will be centrifuged for all phannacokinetic samples. The collected 
blood samples will be kept on ice-packs until centrifugation. The samples will be 
centrifuged within 45 minutes ti·om the scheduled blood sample collection. The 
samples will be centrifuged at the set conditions of 4000 rpm for I 0 minutes at 
4°C to separate plasma. The separated plasma will be transferred to pre-labeled 
polypropylene tubes in two equal aliquots. 
The plasma samples will be then stored upright in a box containing dry ice or in a 
freezer at a temperature of -20 ± 5°C for interim storage (pre-dose and post-dose 
samples up to 4.00 hours) and then will be transferred to -70 ± l5°C at the clinical 
site. 
The plasma samples will be transferred from cold chain management (CCM) 
department to bioanalytical facility for analysis batch wise as per approved 
sequence schedule, after the completion of clinical phase. 
In case meal, urine collection, blood sample collection timings, ECG and vital 
signs coincide, blood samples first and then Urine sample, vitals, ECG followed 
by meals. 
6.5 
Blood Loss 
+ 
+ 
+ 
The total blood loss per subject in the study will not exceed 292 mL for 
male/post-menopausal female subjects and 296 mL for female subjects of child 
bearing potential. In addition to the above, about 3-5 mL of blood will be 
collected for repeat post study safety assessment whenever needed or as decided 
by the Physician/Clinical Investigator/Principal Investigator. 
PK samples for two periods (50 samples of 5 mL each) 
250mL 
Discarded heparin containing blood for two periods ( 40 x 0.5 mL) 
20mL 
Blood withdrawn for screening 
09 mL 
Blood sample collection for Creatinine clearance and serum 
06 mL 
potassium for two periods (02 x 03 mL) 
+ Blood sample collection for post-study safety assessment 
07mL 
Total Blood Loss for male/post-menopausal female subjects 
292 mL 
ASAVi iNSTiTUTIONAL 
ETHtp:S £0fb'l~~jT\fC C !P-SPI-001; Version 02; Date: 07 Aug 2018 
Page 43 of83 
ro oco 
o.. -
'P 0 ~rlVED 
-·\·'"" ~· 
::-\~:..# , 
' 


Protocol 
1~)r Drug-Drug lnteraction Study of Spin)nolactonc and D1goxin (Fasting 
Condition) 
Contidcntial 
---- -- -------------~---------~-----~--------------
--
---
-~-------- --------
+ Serum pregnancy test t(Jr two periods (2 x 02 mL) 
04 mL 
··---·--
Total Blood Loss l(>r female subJects of child bealing potential 
296 mL 
6.6 
Diet and Water 
Subjects will be fasted for at least I 0.00 hours prior to drug administration on 
each dosing day. Standard diet will be provided in each period to all subjects. 
Day 1 to Day 9 (except on Day 6): 
On each day from day I to day 9 (except on Day 6), the standard breakfast, 
Lunch, Snacks and dinner will be served at 0.50, 4.00, 8.00, and 12.00 hours post 
dose. 
Day 6: On day 6, lunch, snacks and dinner will be served at 4.00, 8.00, and 12.00 
hours post dose. 
Note: 
• 
On Day 6, subjects will be fasted for at least I 0.00 hours prior to dosing. 
;---·-----
I 
Days 
Breakfast 
~ 
~ 
Lunch 
Snacks 
Dinner l 
I 
Time post dose (hours) 
Day I to Day 5 
0.50 (30 min) ! 04.00 
08.00 
12.00 
Day6 
NA 
1---
04.00 
08.00 
12.00 
Day 7 to Day9 
0.50 (30 min) 
04.00 
08.00 
12.00 
Dinner on dav '5' will be completed at least 10.00 hours prior to dosing 
Water wilt be provided ad libitum dming the study, except one hour before and 
one hour after dosing on Day 6. 
Note: On all days' subjects will be instructed to consume more water (i.e. at least 
4-5 liters per day) to control the hypotension and volume depletion. 
6. 7 
Total duration of subject participation in the study 
• 
Screening: Screening will take place within 28 days betore the start of the 
study. 
• 
Dosing: Day I to 9 in each period (Including a gap of at least 28 days between 
two successive treatment schedules of the study as wash out period) 
• 
Follow up: Adverse event will be considered as related to the study if noticed 
or repot1ed before study completion date and will be followed up till 
resolution. 
'NSTITUTIONAL 
I 
i 
, r·, H;r:SffaM[M\~~: C CMP-SPI-001; Version 02; Date: 07 Aug 2018 
IAPP~:tOVED 
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!<.-=•"'"''-'<•-


Protocol lOr Drug-Drug lntcractiun Study of Spirnnoladonc and Digoxnl (Fastmg 
Condition) 
Confidential 
• 
The study duration will be !(Jr approximately 39 days, which shall include 
from period I check-in to post study safety assessment of the study. 
6.8 
Maintenance of Study Treatment Randomization Schedule 
The randomization schedule will be made available to the treating physician, the 
Principal Investigator, the Sponsor, the IEC and/or the Regulatory Authority in 
case of any serious adverse event to ascer1ain the treatment allocation. 
6.9 
Documentation of Study Activities 
All the study related activities will be entered directly in the individual activity 
fonns. All the raw data and source documents will be compiled as such. 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
All subjects will undergo a screening procedure comprising of clinical 
examination, recording of electrocardiogram, 20 Echocardiogram, and laboratory 
investigations of blood as well as urine, which will be valid for the number of 28 
days from the day of screening. Radiological investigations (Chest X-Ray) will be 
repeated, if not done in the past 6 months or, if clinically indicated at the time of 
screening. The subjects will be selected on the basis of the following inclusion and 
exclusion criteria. 
7.1 
Subject Inclusion Criteria 
• 
Healthy human subjects aged between 20 and 35 years (including both). 
• 
Subjects with a BMI between 18.5 - 24.9 Kg/m2 (including both) but body 
weight not less than 60 Kgs. 
• 
Subjects who were screened at least 48 hours prior to check-in 
• 
Subjects with nonnal health as determined by personal medical history, 
clinical examination, and laboratory examinations including serological tests 
during the screening as per section I 1.2 
• 
Subjects with nonna1 20 echo 
• 
Subjects having normal 12-lead electrocardiogram (ECG) or ECG with no 
clinical significant abnormalities as detennined by Investigator. 
• 
Subjects having nonnal chest X-Ray (PIA view) or chest X-ray with no 
clinically sil,'llificant abnom1alities as determined by investigator. 
~-;;•:;;··;,;c 7;';7111';
1
~i):jtJfe!:;·ts able to communicate effectively. 
"'rhltMM1J.M.Ec_ 
[8 __ .. Pf~OVED 
MP-SPI-001; Version 02; Date• 07 Aug 2018 
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Protocol f()r Drug-Drug Interaction Study of Spironolactone and Digoxin (Fasting 
Condition) 
Con1ident1al 
• 
Subjects willing to give written informed consent and adhere to all the 
requirements of this protocol. 
• 
Additional inclusion criteria for female subjects, 
~ Female of childbearing potential practicing an acceptable method of bi1th 
control for the duration of the study as judged by the investigator(s), such 
as condoms, foams, jellies, diaphragm, intrauterine device (IUD), or 
abstinence: or 
~ Postmenopausal for at least I year, or 
~ Surgically sterile (bilateral tubal ligation, bilateral oophorectomy or 
hysterectomy has been perfonned on the subject). 
7.2 
Subject Exclusion Criteria 
• 
Subjects having contraindications or hypersensitivity to study drug or related 
group of drugs. 
• 
History or presence of any medical condition or disease according to the 
opinion of the physician. 
• 
History or presence of significant cardiovascular, pulmonary, hepatic, renal, 
gastrointestinal, endocrine, immunological, dermatological, neurological or 
psychiatric disease or disorder. 
• 
Subject having QT/QTc interval >450 milliseconds 
• 
History or presence of significant alcoholism or drug abuse in the past one 
year. 
• 
History or presence of significant smoking (more than I 0 cigarettes or beedies 
/day or consumption of tobacco products). 
• 
Subjects who fail to abstain from consuming any alcoholic products from 
48.00 hours prior to check-in to till check-out /last sample of the study. 
• 
Subjects who fail to abstain from any xanthine-containing food and/or 
beverages (like chocolate, tea, coffee, cola drinks), cigarettes and tobacco 
containing products and grapefruit and/or it's juice from 48.00 hours prior to 
check-in to till check-out /last sample of the study. 
Page 46 of83 


Protocol for Drug-Drug Interaction Studv of Spironulactom.' and Dtgoxin (fasting 
Condition) 
Confidential 
---··············--
. -------··· 
• 
Subjects who tail to rcti·ain from pan or pan masala, gutkha, masala 
(containing beetle nut and tobacco) t(H· 48.00 hours prior to check-in to till 
check-out/last sample ofthe study. 
• 
Ditliculty with donating blood. 
• 
Systolic blood pressure less than II 0 mm Hg or more than 140 mm Hg. 
• 
Diastolic blood pressure less than 70 mm Hg or more than 90 mm Hg. 
• 
Pulse rate less than 60 beats/minute or more than I 00 beats/minute. 
• 
Use of any prescribed medication dwing last two weeks or OTC medicinal 
products/ herbal products during the last one week prior to check-in. 
• 
Major illness during 90 days before check-in. 
• 
Participation in a drug research study within past 90 days of check-in. 
• 
Donation of blood (i.e. one unit or 350 mL) in the past 90 days before check-
111. 
• 
History of unusual diet consumption in the past 3 weeks before check-in. 
• 
Additional exclusion criteria for female subjects, 
:» Volunteer demonstrating a positive pregnancy test. 
:» Volunteers who are pregnant, currently breast-feeding or who are likely to 
become pregnant during the study. 
:» Volunteers who have used implanted or injected hormonal contraceptives 
anytime during the 6 months prior to study or used hormonal 
contraceptives within 14 days before dosing. 
7.3 
Criteria for Discontinuation of the study 
The Sponsor reserves the right to discontinue the study at any time. The Principal 
Investigator reserves the right to discontinue the study for safety reasons at any 
time. The IEC may ask to tenninate the study, if there are major violations of the 
ethical considerations or due to any serious adverse event(s). Reasons for the 
termination of the study will be provided to the subjects. 
7.4 
Tests to be performed before Check-in of the study 
Subject's urine (approximately 20 mL) will be screened for drugs of abuse like 
cocaine, cannabis, amphetamines, barbiturates, benzodiazepines and opiates at the 
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Page 47 of83 


Protocol f()J Drug-Drug 
Intcr<~ction Study of Sp1n1nolactonc and D1goxin (Fasting 
Conthtion) 
Conlldcntwl 
time of each check-in of study. Subject will be rejected/ withdrawn li·om the study 
at any point of the time if the result is positive f(n· these drugs. 
Alcohol breath test will be performed for all subjects bet(1rc check-in into each 
period of the study. Subject will be rejected/withdrawn from the study if the result 
is positive for alcohol. 
Serum Pregnancy test (f3-hCG) will be pcrfonned for all the female subjects 
having child bearing potential and urine pregnancy test will be perfonned for post-
menopausal subjects at every check in. Subjects will be rejected/withdrawn from 
the study if result is positive for pregnancy at any point of time. 
7.5 
Subject Withdrawal Criteria 
7.5.1 
Procedures to Withdraw Subjects from the Investigational Product 
Treatment 
• 
Subject wishes to withdraw consent on his own accord in person and the same 
will be considered as dropout. 
The Principal Investigator/Clinical Investigator may withdraw a subject from the 
study for any ofthe following: 
• 
The subject is non-cooperative and non-compliant. 
• 
The subject is found to have entered the study in violation of this protocol. 
• 
If any subject experience emesis at or before 2 times of median T max on Day 6. 
• 
The subject is suffering from any other clinically significant adverse event. 
• 
The subject who receives/requires any concomitant medication, which may 
interfere with the phannacokinetic property of the study drug. 
• 
The subject who underwent/requires hospitalization during the course of the 
study. 
• 
The subject reported to the clinical facility for check-in after the prescribed 
time limit there by failing to meet the protocol requirements. 
• 
If it is felt in the investigator's opinion that it is not in the subject's best 
interest to continue. 
• 
The subject is tested positive for Alcohol breath test. 
• 
The subject is tested positive for any one of the urine drugs of abuse. 
• 
Subjects who miss 03 consecutive blood draws in a study period. 
J<§, ..... ,..._,..._,.,..._,._,_.. ... ""'""" ........ 
f: VAS."\ i H\l 
! 
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-SPI-00 I; Version 02; Date: 07 Aug 2018 
Page 48 of 83 
! 
'""".' -, .''' <A>• \ IE D 
;.,~: ___ "t~ Jt·:l;~u v 


Protocol l(n Drug-Drug lnkraction Study of Spin.molactone and Digoxin (Fastmg 
Condition) 
Confidential 
7.5.2 
The Type and Timing of the Data to be collected for Withdt·awn Subjects 
Any subject withdrawal during the study along with the reason thereof shall be 
documented in the Fonn tor Subject Withdrawal/ Drop out Record, as per 
applicable ClinSync SOP. 
The samples of subjects withdrawn due to adverse events will also be analyzed. 
Plasma concentration vs. time data of that subject will be tabulated separately and 
repot1ed in the study report and will not be included in phannacokinetic and 
statistical analysis. 
The concentrations of Unchanged drug excreted in urine/ Amount Recovered for 
digoxin will be tabulated separate! y and reported in the study report for all 
withdrawn subjects due to adverse events. 
7.5.3 
Replacement of Subjects 
No dosed subject will be replaced. 04 additional standby subjects will be enrolled 
to ensure dosing 28 subjects in period !. Any subject withdrawn/dropped out from 
the study due to any reason prior to dosing of period I will be replaced by stand-by 
subject. If there are no dropouts, these 04 standby subjects will be checked out 
after completion of 28 subjects dosing in period I. All details will be documented 
appropriately. 
Note: In period I, two standby subjects will be checked out from the study on day 
1 after completion of the dosing activity and remaining two standby subjects will 
be checked out from the study on day 6 after completion of the dosing activity. 
7.5.4 
The Follow-up for Subjects Withdrawn from Investigational Product 
Treatment 
Any subject withdrawn during fhe study due to any adverse event will be followed 
up wherever possible till resolution or until the physician believes that there will 
be no further change. This may involve additional visits. 
7.6 
Restrictions 
7.6.1 
Diet 
Subject should not take any unusual diet (for e.g. low salt diet) at least 3 weeks 
prior to check-in and throughout the study. 
t·\f!.;S:t.\\/[ 1N~T~TUTIONAL 
Page 49 of83 
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\Af:'L -~-'_&3'f!t)· C-CMP-SPJ-001; Version 02; Date: 07 Aug 2018 


y:i 
Protocol f(n Drug-Drug Interaction Study of Spironolactone and DigOXIn (F:Jsting 
Condition) 
Confidential 
Subjects will be instwctcd to abstain ti·om consummg any alcoholic products fi·om 
48.00 hours prior to check-in to till check-out I last sample of the study. They will 
not be allowed to have any xanthine-containing food and/or beverages (like 
chocolate, tea, coffee, cola drinks), cigarettes and tobacco containing products and 
grapefruit and/or it's juice from 48.00 hours prior to check-in to till check-out I 
last sample of the study. 
7.6.2 
Posture 
Subjects who are dosed will remain Ill a supine position or semi recumbent 
position for 03 hours post-dose on Day 06 and only necessary movement will be 
allowed during this period. Thereafter subject will be allowed to ambulate freely 
during the remaining part of the study. Subject will not be allowed to sit down 
(except as directed by the physician secondary to adverse events) during 
restriction period. 
Note: 
• 
In case any subject has any adverse event and requires any change in 
restrictions of water & posture, it will be done after consultation with the 
Principal investigator/ Attending Physician. 
• 
During the posture restriction period all study related activities (Blood and, 
vital signs measurement) will be done at bed side only, except urine sample 
collection. 
7 .6.3 
Medication 
S\Jbjects will be instructed not to take any prescription medications within two 
weeks prior to check-in and throughout the study. Subjects will be instructed not 
to take any OTC products, herbal medications, etc. within one week prior to 
check-in and throughout the study. If these medications are required, subject will 
not be enrolled or may be withdrawn from study by investigator. 
7.6.4 
Others 
Subjects will be instructed to refrain fi·om pan or pan masala, gutkha, masala 
(containing beetle nut and tobacco) for 48.00 hours prior to check-in to till check-
out/last srunple of the study. 
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;: 
yn 
Protocol for Drug-Drug lnternction Study o!' Spironolactone· and Digoxin (Fasting 
Condition) 
Coniiclcntial 
8 
BIOANALYTICAL PROCEDURES 
8.1 
Method Description 
a. The bioanalytical method will he developed & validated by using LC -MSIMS 
tor quantification of digoxin in presence of spironolactone and canrenone as 
per current version of in-house SOP "Bioanalytical Method Validation" and 
applicable regulatory requirements. 
b. Samples will be assayed for digoxin in presence of spironolactone and 
canrenone using the validated method at ClinSync Clinical Research Pvt. Ltd., 
Hyderabad. 
c. Unchanged drug excreted in unne for digoxin will be analyzed by using 
validated LC-MS/MS method. 
d. Analysis of the plasma will include distribution of quality control samples 
throughout each batch of study samples. All the available plasma samples will 
be analyzed in bio-analyticallaboratory. 
e. However, the samples of all withdrawn and dropped out subjects will be 
analyzed and tabulated in a separate table. 
f. 
The analyst will not have access to the randomization code list during the 
course of the analysis. 
g. All concentration values below the limit of quantification (BLQ) will be set to 
zero for obtaining descriptive statistics. All zero pre-dose concentrations will 
not be reported as BLQ 
h. Whenever possible, all samples from each subject will be analyzed on the 
same standard curve. Samples with drug concentration greater than the upper 
limit of the validated range of the assay will be diluted with the appropriate 
drug-free biological fluid and method validation and repeat analysis will be 
done as per the current version of applicable ClinSync SOP. 
1. 
Incurred sample reanalysis (JSR) will be performed as per cun·ent version of 
applicable ClinSync SOP. 
9 
PHARMACOKINETIC ASSESSMENTS 
Concentration data of subjects versus time, which are received atier analysis of 
···-· -·--· 
samples, will be included in the final data analysis. Data from subjects with 
j v~~j./~,~~~.~~M 
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Protocol for Drug-Drug Interaction Study of Spironnlactunc and Digoxin (Fasting 
Condition) 
Confidential 
missing concentration values (missed blood samples, lost samples, samples unable 
to be quantified) may be used if pharmacokinetic parameters can be estimated 
using remaining data points, otherwise data from these subjects will be excluded 
tl-om the final analysis. 
All concentration values below the limit of quantification (BLQ) will be set to 
zero for all phannacokinetic and statistical calculations. Any missing samples will 
be repot1ed as 'Missing' and will be denoted as "M" while running 
pharmacokinetic and statistical analysis. 
The following phannacokinetic parameters will be computed usmg non-
compartmental model of Phoenix WinNonlin Professional Software Version 6.4 
(Pharsight Corporation, USA) or above. 
Phannacokinetic Parameters for digoxin in plasma: 
Primary Phannacokinetic parameters 
AUCo-96 
Maximum measured plasma concentration. 
Area under the plasma concentration versus time curve 
from time 0 to the 96 hour time point concentration, 
calculated by linear trapezoidal method. 
Secondary Phannacokinetic parameters 
Tmax 
Time to achieve maximum plasma concentration. If the 
maximum value occurs at more than one time point, T max 
is defined as the first time point with this value. 
Pharmacokinetic Parameters for digoxin in urine: 
Renal clearance AC0-24oh/ AUCo-240 h 
Unchanged dmg excreted in urine 
For all the above computations, actual time points of the sample collection will be 
used in case of sample collection deviations. 
In clinical phase or sample analysis process, if 3 or more consecutive post dose 
samples for any subject are found to be missing, samples of such subjects will be 
analyzed but phannacokinetic data of those subjects will be excluded from the 
final statistical analysis. 
VAS/WI INSTITUTIONAL 
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Prot<xol for Drug-Drug Interaction Study of Spironolactonl:'" and Digoxin (Fasting 
Condition) 
Coniidcntinl 
Phannacokinctic data of those subjects will be tabulated and rcpoticd in the study 
report as a separate table. However, the data of such subjects will also be 
considered for statistical analysis if the 3 consecutive post dose samples are the 
last three samples of elimination phase. 
If the pre-dose concentration appears to be > 5% of the Cmax in any subject at any 
period, the data of such a subject will be excluded from the statistical analysis. 
10 
STATISTICAL ANALYSIS 
Statistical analysis will be perfonned by using SAS statistical software version 9.3 
or above. 
Descriptive statistics of all the phannacokinetic parameters will be computed and 
reported for digoxin. 
10.1 
Number of subjects 
A total number of 28 healthy adult human subjects will be enrolled in the study. 
Additionally, 04 stand-by subjects will be included in order to dose 28 subjects in 
period I. As the same perpetrator (LANOXJN® Tablets USP 250 meg) will be 
given to both the treatments and only the difference is going to be with and 
without spironolactone oral suspension, 28 subjects along with 04 stand-by 
subjects will be suftlcient to provide a reliable estimate of the magnitude and 
variability of the interaction. 
10.2 
Analysis of variance 
The Jog-transfonned phannacokinetic parameters (Cmax and AUCo-96) will be 
analyzed using Type Ill sum of squares, with the main effects of formulation, 
period, sequence and subjects nested within sequence as random effect. A separate 
ANOVA model will be used to analyze each of the parameters. The sequence 
effect will be tested at the 1 0% level of significance using the subjects nested 
within sequence mean square as the error tenn. Formulation and period effects 
will be tested at the 5% level of significance against the residual en·or (mean 
square etTor) from the ANOV A model as the en·or term. Each analysis of vatiance 
will include calculation of least-squares means, the difference between the 
adjusted fommlation means and the standard error associated with the difference. 
!Vii.A\Ssj;A;\;v0; ~::T;,S'. Tn!TT. i\11~lii1!"'1 analyses will be done using the approptiate SAS' procedure. 
i ETH'G-"'·-tt*"!MI'Ff#-1------------------------------
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Protocol li1r Drug-Drug Interaction Study of Spmmolactonc and Drgoxin (Fasting 
Condition) 
Confidential 
10.3 
Two one-sided lest for biocquivalence 
Two one-sided test (Schuinnann's test, 1987) for bioequivalencc and 90% 
confidence intervals f(lr the ratio of least squares mean between drug formulations 
will be calculated, for In-transformed data of C,,.,_, and AUCo-96. 
10.4 
Power 
The power of a test to detect 20% difference between treatment A & B will be 
computed and reported. 
10.5 
Ratio analysis 
The comparison of interest is Treatment (A) Vs Treatment (B), so the ratios will 
be of the fom1: Treatment (AlB). 
Ratio of least squares means of Treatment A & B will be computed for ln-
transfOimed pharmacokinetic parameters Cmax and AUCo-96. Ratio analysis will be 
reported in percentage for ln-transfonned pharmacokinetic parameters (Cma< and 
AUCo-96) for Digoxin. 
10.6 
Intra-Subject Variability 
Intra-Subject variability will be computed for In-transformed pharmacokinetic 
parameters (Cmax and AUCo-96) for Digoxin. 
I 0. 7 
Criteria for evaluation 
The presence or absence of DDI between two treatments (A and B) will be based 
on the statistical results of 90% confidence interval for the ratio of the geometric 
least squares mean for log-transfonned phannacokinetic parameters C,,, and 
AUCo.96 for Digoxin. 
Absence of drug-dnrg interaction will be established if the 90% CI for the ratio of 
population geometric means between two treatments (A and B), based on log-
transformed data, present in the equivalence limits of 80.00- 125.00% for C.nax 
and AUCo-96· 
Summary statistics of phannacokinetic profile of Digoxin (substrate drug) in the 
presence and absence of spironolactone (perpetrator) will be provided based on 
plasma and urine data. Renal clearance (CLR)/ Percent Recovered and unchanged 
drug excreted in urine (fe)/Amount Recovered tor Digoxin will also be measured 
Page 54 of83 


Protocol for Drug-D111g Interaction Study of Spironolactone and Digoxin (Fastmg 
Condition) 
Conlidcntial 
Il 
ASSESS111ENT OF SAFETY 
l 1.1 
Specification of Safety Parameters 
Vital signs (seated blood pressure, radial pulse rate and oral/aural temperature) 
will be measured as per section 11.2. 
I 1.2 
Methods and Timing for Assessing, Recording and Analyzing Safety 
Parameters 
Clinical examination along with vital signs (seated blood pressure, radial pulse 
rate and oral/aural temperature) measurement will be can·ied out and recorded at 
check-in and at checkout of each period and/or at the tennination of the study. 
Clinical examination will be can·ied on prior to dosing on day 06 in each study 
period. 
Oral/aural temperature will be measured prior to dosing. 
Vital parameters - seated blood pressure and radial pulse rate will be measured at 
prior to dosing, 1.00, 3.00, 5.00 and ll.OO hours post dose in each period from 
Day 1 to Day 5, whereas from Day 6 to Day 9, vitals will be measured at prior to 
dosing, 1.00, 2.00, 3.00, 5.00, 8.00 and 11.00 hours post dose in each period. A 
window period of± 45 minutes from the scheduled time point is allowed for post 
dose vitals recording. 
ECG Measurements: 
• 
ECG will be perfonned before period II check in and subject study eligibility 
will be assessed as per the principal investigator discretion. 
• 
ECG will be perfonned at 1.00 and 3.00 hours post dose in each period on 
Day 6 with a window period of± 45 minutes fi·om schedule time. 
• 
ECG will be perfonned at check-out of each period of the study. 
Note: 
• 
On Day 6 the Vital sings (i.e. up to 3.00 hours post dose) will be perfonned at 
bed side only. 
• 
2D echo will be perfonned at the time of screening. 
• 
Dosing will be done under the supervision of cardiologist. 
• 
For subjects who are randomized to treatment A, the vitals will be checked at 
5.00 hours post dose during day I to Day 5. However, the vitals time points 
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Protocol i\1r Drug-Drug Interaction Study or Spironolactone and D1goxin (Fasting 
Condit JOn) 
Confidential 
will be similar fi·om day 6 for treatment groups A and 1:3. 
Vital signs may also be carried out at any time during the conduct of the study if 
the attending physician feels it necessary. ln case of abnonnality in vital signs 
during pre-dose vitals, recording, medical opinion will be taken whether to dose 
the subject or not. 
Additional Laboratory evaluations (Biochemistry): 
ln each study period creatinine clearance and serum potassium levels to be 
measured on day 05 and the dosing eligibility of the subjects will be done as per 
the principal investigator discretion. 
Risk evaluation and mitigation strategy: 
Since healthy subjects are being enrolled in the study, there is no benefit to them. 
In general, the adverse reactions of digoxin are dose-dependent and occur at doses 
higher than those needed to achieve a therapeutic effect. Hence, adverse reactions 
are less common when digoxin is used within the recommended dose range or 
therapeutic serum concentration range and when there is careful attention to 
concurrent medications and conditions. 
As Digoxin is a narrow therapeutic index drug, the drug administration will be 
done under the supervision of a cardiologist along with a continuous close 
monitoring by medical and para medical personnel. Since most of the digoxin is 
excreted unchanged in the urine, subjects with significant difference from nonnal 
serum creatinine or creatinine clearance values will not be considered for this 
study. In addition, only the subjects with no1mal2D echo and QTc interval will be 
enrolled into the study. 
Considering the single dose nature of this study and 28 days washout period 
between dosing periods, the effects caused by 250 meg Tablet of Digoxin are not 
expected to impact on safety in the healthy volunteer population. Even if adverse 
events are observed, they are likely to be benign, transient, not require 
intervention. Nevertheless, close monitoring of blood pressure, pulse rate, and 
ECG will be conducted dming the time maximum phannacodynamic effects are 
observed (i.e. during I - 3 hours post dose). 
/
rVA-S''' · .· 
Furthennore, subjects will be domiciled until day 04 (i.e. until 96 hours after drug 
,., . f !~iSTITUTION'L 
ETHIC'' 
·"' 
.v: 
1• 
EE 
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Protocol f(H Drug-Drug Interaction Study of Spirontllactonc ;md Digoxin (Fasting 
Condition) 
Conlidcntial 
administration in each period), thus providing an optimal setting for the clinical 
monitoring and~ if necessary, management of any adverse events. 1-hn:vcver, 
subjects will only be allowed to leave the clinical center after clinical 
examination, ECG, and other safety measures are repeated at the end of study 
visit. 
KCllnjcction, KCl oral Syrup, Amiodarone Injection 150 mg, Xylocard Injection 
will be made available in the JCU at the time of study as a precautionary measure. 
Overall, based on the known AE profile of 250 meg Tablet of Digoxin, strict 
screening. inclusion and exclusion criteria, routine safety assessments and 
planned close monitoring of known AE's, blood pressure, pulse rate, ECG, and 
28 days washout period is considered sufficient to mitigate any potential risk to 
the subjects. 
Laboratory evaluations performed during screening are asfollows: 
I Blood tests: 
Hematology 
Biochemistry 
nne ana ysts 
u· 
Hemoglobin 
Random blood glucose 
Physical Examination 
Total RBC Count 
Blood urea 
Chemical Examination 
Total WBC Count 
Serum creatinine 
Microscopic examination 
Platelet count 
Serum uric acid 
Differential count 
Serum sodium 
Peripheral smear 
Serum potassium 
Blood group 
Serum chloride 
! 
ESR 
Serum calcium 
Serum magnesium 
Serology: 
Liver Function Tests: 
I 
HIV 
(l 
& 
2) I 
Total Bilirubin 
antibodies 
Direct Bilirubin 
I 
I HBsAg 
(Hepatitis I 
SGOT (AST) 
Bsurface antigen) 
SGPT (ALT) 
I 
Anti-hepatitis 
C I 
Alkaline phosphatase 
Virus (HCV) 
Total proteins 
VDRL (RPR) 
I 
Albumin 
Total Cholesterol 
I 
Note: The laboratory parameters wtll be evaluated as per laboratory reference 
ranges (Appendix-JV). In rare instances, when the values are out of laboratory 
P-SPI-001; Version 02; Date: 07 Aug2018 
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I 


Protocol f(Jr Drug-Drug lnteractinn Study of Spironolactone and Digoxin (Fasting 
Condition) 
Contldcntial 
reference ranges, then those values will be cotTclatcd with clinical condition of the 
subject for fut1her evaluation. 
LaboratOIJ' (safi;:ty} emluarions performed at/he end o{srudv: 
About 07 mL of blood will be collected from each subject for safety evaluation 
[which includes hematology (except blood group and Rh typing) and 
biochemistry (except random blood sugar) as per section 11 .2] at the end of the 
study. If the subject does not come tor the safety evaluation on scheduled time for 
any reason, follow-up will be done as per applicable Clinsync SOP. 
11.3 
Handling and reporting of Adverse Events and Serious Adverse Events 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a patient or 
clinical investigation subject administered a phannaceuticaJ product and that does 
not necessarily have a causal relationship with this treatment An AE can therefore 
be any unfavorable and unintended sign (including an abnonnal laboratory 
finding), symptom, or disease temporarily associated with the use of a medicinal 
(investigational) product whether or not related to the medicinal (investigational) 
product. 
Adverse Drug Reaction (ADR): A response to a drug which is noxious and 
unintended and which occurs at doses nom1ally used in man for prophylaxis, 
diagnosis, or therapy of disease or for modification of physiological function. 
Unexpected Adverse Drug Reaction: An adverse reaction, the nature or severity 
of which is not consistent with the applicable product information of Carospirlt 
Spironolactone Oral Suspension, 25 mg/5 mL 
Serious Adverse Event (SAE): A serious adverse event (experience) or reaction 
is any untoward medical occurrence that at any dose 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires inpatient hospitalization or causes prolongation of existing 
hospitalization, 
• 
Results in persistent or significant disability/incapacity, 
•r· \ilt'liA~<;AAiilti'ii:. -;;::;:;:;::=,..-._.Congenital anomaly/birth defect, 
I .. ;2" ' : iNSTiTUTIONAL 
J 
c Y"H!r~<, COlt, !1', =,rn::r'=-t-------------------------------
{A. ~} 
f~Qt~ie N 
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·----·· 


Protocol fln Drug-Drug lnicradion Study of Spironolactone and Digoxin (Fnsting 
Condition) 
Confidential 
• 
Requires intervention to prevent pennancnt impairment or damage 
Note: The tenn "lite threatening" in the definition of "serious adverse event" 
refers to an event in which the subject was at risk of death at the time of the event; 
it docs not refer to an event, which hypothetically might have caused death if it 
was more severe. 
The causality assessment to the study treatment is characterized as: 
I 
jTERM 
Certain/ 
Definite 
I 
Probable/ 
I 
DESCRIPTION 
-y~------~c--,-~~-~--~--, 
I 
COMMENT 
A 
clinical 
event, 
including! It is recognized that this stringent 
test 
abnonnality, definition will lead to very few 
laboratory 
occurring in a plausible time repot1s meeting the criteria, but this 
relationship 
to 
drug is useful because of the special valuej 
administration, and which cannotj of such reports. It is considered that 
be 
explained 
by 
concurrent! time relationships 
between 
drug 
disease 
or 
other 
drugs 
or: administration and the onset and 1 
chemicals. 
The 
respon:e 
toj course of the adverse event are 
withdrawal 
of 
( dechall enge) 
the 
should 
drug important in causality analysis. So, 
be also 
is 
the 
consideration 
o 
clinically plausible. The event confounding features, but due weight 
must 
be 
definitive must be placed on the known 
phannacologically 
or pharmacological 
and 
other 
phenomenologically, 
using 
a characteristics of the drug product 
satisfactory 
rechallenge, being considered. Sometimes the 
will I 
procedure if necessary 
clinical phenomena described 
also be sufficiently specific to allow 
/a confident causality assessment in· 
the absence of confounding features 
and 
with 
appropriate 
time 
relationships, 
. anaphylaxis. 
I 
e.g . 
penicillin 
A 
clinical 
event, 
including This definition has less stringent 
I VASAV'!! !itrj, iJLJ:ik0
e5'lfly'3liiAJ;::J:~l=ab::::o::::r::::a::::to::::r::y::::t::::e::::s::::t ::::a::::bn::::o::::n::::n::::a::::l::::it=y=, ::::\\=·i=th:!=w::::·o=r=d=in~g=th::::a::::n=fo::::r=" c::::e::::rt::::a::::i::::n_::::" ::::a::::n::::d::::d::::o::::e::::s~~-­
l Eli-i'CS (f9Ml'OOT1llf6.: 
I A p ~:::~ '" f'"H!fD 
L!:L. ___ !.,_ :_~-".,..· _'>.~~::..:=;..~ 
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I 
Protocol for Drug-Drug Interaction Study of Spironolaclone and Digoxin (Fasting 
Condition) 
Confidential 
r- -------~a iei,$0,;a],Je (j;11cseq~~~~;:-(olnc;;-;1eces~it:1rc-p;:T;;,:-jmm~T~dge·- ofj 
) 
I administration 
of the 
drug,,drug 
characteristics 
or 
clinical/ 
I 
/unlikely to 
be 
attributed 
to/adverse reaction 
phenomena. Asj 
, 
I 
concun-ent disease or other drugs/ stated no reclwllcnge infonnation is) 
1 or chemicals, and which follows, needed, 
but 
confounding 
drug/ 
Possible 
Unlikely/ 
Remote 
1 
I 
. 
I a clinically reasonable response! administration 
underlying 
diseasej 
lou 
withdrawal 
(dechallenge). must be absent. 
/ 
Rechallenge infonnation is not 
1 
required to fulfill this definitiOn. 
A 
clinical 
event, 
including' This is the definition to be used j 
laboratory test abnonnality, with when dmg causality is one of other// 
a reasonable time sequence to possible causes for the described, 
administration of the drug, but/ clinical event. 
, which could also be explained by/1 
concurrent disease or other dmgs 
or chemicals. Information on 
I 
drug withdrawal may be lacking 
or unclear. 
A 
clinical 
event, 
including This definition is intended to be used 
laboratory test abnormality, with when the exclusion of dmg causality 
a temporal relationship to drug. of a clinical event seems most 
administration which makes a plausible. 
causal relationship improbable, 
and 
m 
which 
other 
drugs,/ 
chemicals or underlying disease! 
provide plausible explanations. 
! 
I 
Conditional/ A 
clinical 
event, 
including 
I Unclassified 'laboratory 
test 
abnonnality,/ 
I 
reported as an adverse reaction, 
about 
which 
more 
data 
is 
f \!ASAVI iN TITUT 
essential for a proper assessment! 
l.iAE:~"l.f.::.s ::;;p:;.;.·r·· ~:-':~7'.~-:-"IJjTl>. 
l""m""'",.-. t_'--C-M_P ___ S_P_I--0-0-l ;_V_e_r-si_o_n_0_2_; -D-at_e_: '--07_A_u_g_2_0_18-----P-ag_e_6_0_o_f_8..J.3 __ 
I 
t"*'f~#'1' 'ED 
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Protocol f()r Drug-Drug lntcraction Study of Spironolactone <llld Digoxm (Fasting 
Condition) 
Contidential 
~-
-
~---
1 
lor the additional data are under! 
, 
. 
examination. 
______ j_ 
I 
Unasscssible/ lA report suggesting an adverse· ---
'Unclassifiabl reaction which cannot be judged 
... I 
e 
because 
information 
isj 
insufficient or contradictory, and I 
which cannot be supplemented or/ 
veritied. 
. 
' 
I 
For each adverse event, the following information must be recorded in 
individual AE reporting forms: 
• 
Type of adverse event 
• 
Is it serious or non-serious? 
• 
Date and time of onset 
w 
Date and time of resolution 
• 
Severity (mild, moderate or severe) 
• 
Association with the study medication (remote, possibly related, probably 
related or definitely related) 
• 
Action taken 
• 
Outcome of adverse event (resolved or unresolved) 
• 
Further details of the AE, if any. 
Intensity of adverse events will be assessed as following; 
Mild: An adverse event, Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated; generally, not interfering with 
nonnal activities. 
Moderate: An adverse event, minimal, local or noninvasive intervention 
indicated; which is sufficiently discomforting to interfere with nonnal activities. 
Severe: An adverse event, which is severe or medically significant but not 
immediately life threatening and does not cause hospitalization or prolongation of 
hospitalization; it incapacitates and prevents nonnal activities. 
Subjects will be monitored throughout the study period for adverse events. 
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ProtncoJ it)r Drug-Drug lntera(.:tiun Study of Spironolactone and Digoxin {Fasting 
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Confidential 
adverse event that may occur during their stay at the chnical facility. 
Subjects will also be specifically asked about any adverse events throughout the 
study period during the recording of vital signs. A medically qualified designate 
will be available round-the-clock dwing the period of housing at the clinical 
facility. The attending physician at the clinical facility will treat all the adverse 
events or serious adverse events. Any AE or SAE if required will be managed in-
house in the well-equipped JCU, available at the study site by qualified physician 
and, if required subject will be transported in ambulance to the tertiary healthcare 
hospital for treatment, with which ClinSync has an agreement in place. 
Recording of Adverse events 
All adverse events including both observed and volunteered ones will be recorded 
on the appropriate AE fonn (As per applicable Clinsync SOP), irrespective of its 
association with the investigational products. Laboratory parameters, which are 
outside the clinically acceptable ranges but are not clinically significant as per PI 
discretion, must be recorded in the lab repott and respective CRF page as Nil 
Significant. Clinically significant abnonnal laboratory values that represent a 
change from baseline should be recorded diagnostically as AE's (e.g.: for elevated 
serum glucose, the AE would be described diagnostically as "hyperglycemia''). 
Detem1ination of Clinical significance is based on the Investigator's medical 
judgment/discretion. PI shall evaluate the event for its sevetity, causality and 
setiousness that require immediate report to IEC and sponsor. 
The institutional ethics committee (JEC), regulatory agency (ies), and the sponsor 
will be inf')fmed regarding the adverse events as necessary. Any serious adverse 
events will be recorded in appropriate Serious Adverse Event Reporting Fonn (As 
per applicable Clinsync SOP). 
The investigator shall report all serious and unexpected adverse events to the 
licensing authority, the sponsor or his representative, whosever had obtained 
permission from the licensing authority tor the conduct of the study and the ethics 
committee that accorded approval to the study protocol, within twenty-four hours 
of their occurrence. In case the Investigator fails to report any serious adverse 
event within the stipulated period, he shall have to fumish the reason for the delay 
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Protocol f()r Drug-Drug Interaction Study of Spironolactone and Digox1n (Fasting 
Condition) 
Confidential 
to the satisfaction of the Licensing Authority along with the report of the serious 
adverse event. The report of the serious adverse event, after due analysis shall be 
forwarded by the investigator to the Licensing Authority, chain11an of the Ethics 
Committee and the Head of the Institution where the trial has been conducted 
within foUJ1een calendar days of the occurrence of the setious adverse event. 
Serious adverse events report submitted to Licensing Authmity will be in color 
coded binding, where the reports of SAEs of Deaths are submitted in red cover, 
the report of SAEs of injury other than deaths in blue cover and the remaining 
cases of SAE report in white cover. 
Each adverse event will be evaluated for duration, sevetity, and action taken, 
outcome and association with the study medication. The study may be suspended 
or ten11inated depending upon the setiousness of the adverse events. 
Note: The reporting of all serious, unexpected suspected adverse reactions, any 
unexpected fatal or life-threatening suspected adverse. reactions and any findings 
from the clinical study will be submitted as a per the timelines mentioned in 21 
CFR 312.32 and 21 CFR 312.33 and compliance with the FDCA (21 U.S.C. §§ 
301 et. seq.). 
11.4 
Type and Duration of the Follow-Up of Subjects 
All adverse events will be followed until resolution or until the physician believes 
that there will be no finther change. This may involve additional visits. Follow up 
will be continued as per applicable Clinsync SOP. 
11.5 
Criteria for the Termination of the Study 
• 
Based on the safety of the subjects, the study can be suspended or terminated. 
• 
The lEC/Sponsor/ regulatory can suspend/terminate the study any time during 
the monitoring due to one of the following reasons: 
a) Non-compliance to Protocol, 
b) Non-compliance to GCP 
c) Non-compliance to applicable regulatory guidelines. 
12 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Direct access to source data/documents will be pennitted to study-related 
monitoting, audits, IEC review, and regulatory inspection(s). 
f\IASP:vt T 
.. 
OJ-·~S:-fi. ·'ftj'ffl:iftitt:t-_:_----------------------------
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Protocol for Drug-Drug Interaction Study of Spironolactone and Digoxin (Fasting 
Condition) 
Confidential 
13 
QUALITY ASSl!RANCF: 
The raw data generated during the course of the study as well as rep011s will 
undergo quality assurance audit for contonnancc to this protocol and all the 
goveming SOPs by auditors fi·om the Quality Assurance Depmiment of ClinSync 
Clinical Research Pvt. Ltd. The final report will contain a statement for quality 
assurance duly signed by auditors and the Head- Quality Assurance. 
14 
ETHICS 
14.1 
Institutional Ethics Committee 
This protocol and corresponding infonned consent torm (lCD) (containing 
information about the study to be given to the subjects) to be used to obtain 
written informed consent of study subjects will be reviewed by the Institutional 
Ethics Committee (IEC) and subjects will not be enrolled into the study until the 
IEC approves the protocol and the !CD as submitted or with modification(s). The 
study will be conducted according to the requirement of the Dedaration of 
Helsinki and ICH guidelines (Step 5) 'Guidance on Good Clinical Practice' and 
'Guidance on Good Laboratory Practice'. 
14.2 
Written Informed Consent 
lnfonned consent should be obtained before conducting any study-specific 
procedures (i.e. all of the procedures described in the protocol). The process of 
obtaining infmmed consent should be documented in the subject source 
documents. 
The Principal Investigator or designated study personnel will infonn the subjects 
(in a language understandable by the subject) before initiation of ;,tudy through an 
oral presentation regarding the purpose, procedures to be carried out, 
investigational products, potential hazards and rights of the study subjects. The 
subjects will be required to understand and sign the !CD obtained prior to any 
study specific screening or other protocol required procedures being conducted. 
and one photocopy of the signed !CD will be given to each subject while the 
original will be filed in the trial master file. 
If a subject is unable to read and write, an impartial witness will be present during 
the entire infonned consent discussion. The infonned consent fonn provided to all 
Page 64 of83 


Protocol f(n Drug-Drug Interaction Study of Spinmolactonc and Digoxin (Fasting 
ConditiOn) 
Contidential 
the subjects will be explained. The written consent will be obtained ii·om all the 
subjects, who are able to read and understand. If any subject(s) is unable to read 
and understand the informed consent, his sign/thumb impression will be obtained 
along with the witness sign and date. 
By signing the consent form, the witness attests that the infonnation in the consent 
form and any other written infonnation was accurately explained to, and 
apparently understood by, the subject and that infonned consent was freely given 
by the subject. 
14.3 
Audio Video Consent 
The Investigator/designee will safeguard the confidentiality of study data, which 
might lead to the identification of the individual subjects. Data of individual 
subjects can be disclosed only in a court of law under the orders of the presiding 
judge or in some cases may be required to communicate to Drug regulatory/Health 
authority. 
In order to maintain the confidentiality, the videographer (person involved in 
recording the audio video consent) will be engaged as part of the study team. Prior 
to initiation of the study, the Investigator/study coordinator will define and 
allocate the activities of audio-video recording of infonned consent process to the 
respective identified person as videographer. 
Prior consent of the subject will be taken for audio-visual recording of infonned 
consent process and the same will be documented by the Investigator. Such 
consent can be taken orally. Only those subjects who give the consent for the A V 
recording shall be included in the study. 
In the present study lntemet protocol camera will be used to record the lnfonned 
consent process in a closed room. The Intemet protocol camera operator may not 
be physically present in the infonned consent room. The recorded data will be 
archived for at least 05 years. 
14.4 
Subject Participation Fee 
The subjects will be paid an adequate (IEC approved) participation fee for their 
participation in the study. In case of dropout/withdrawal of a subject before 
r VA 
completion of the study, the subjects will be paid a pro-rated participation fee 
I 
SAVIINSTITUTIONAL 
' 
ETH
1C'€e~m·~·rorrrn~-1~---------------------------------------------------------
/ ':, p. ~;~~~~"".! ~4;_( -CMP-SP!-001; Version 02; Date: 07 Aug 2018 
Page 65 of83 
I~< •. r "'<~ ~. '-0 
--=-. 
... ~ ~ ' 
:;;, 


Prowcol f()r Dr11g-Drug Interaction Study of Spironoluctonc and Digoxin (Fasting 
Condition) 
Con fidcntJ al 
depending upon the extent of pal1icipation and any controversy pertaining to this 
will be forwarded to the !EC and the decision of the IEC will be final as well as 
binding on both the subjects and ClinS.)11C Clinical Research Pvt. Ltd. 
15 
DATA HANDLING AND RECORD KEEPING 
All data generated during the conduct of the study will be directly entered in the 
respective raw data fonns. The computer-generated randomization schedule will 
also be treated as raw data. All raw data and transcribed data fonns compiled by 
the study personnel involved in the study will be checked for completeness. All 
data related to the project will be in the custody of the Principal Investigator until 
transfen·ed to archives. 
15.1 
Study Report and Documents 
The final report fonnat will be prepared as per JCH E3: Structure and Content of 
Clinical 
Study Reports 
and 
as per CDSCO regulatory requirements. 
Supplementary Documents such as screening records, Period I and Period II 
records etc. will be given along with study report. Frequency distributions of 
gender and race will be tabulated by treatment and sequence. Summary statistics 
for age, body weight, height, and Body Mass Index (BMI) will be tabulated by 
treatment sequence. Listings of pre study & post study laboratory values, listing of 
adverse event by subject, listing of urine drug scan by subject, listings of protocol 
deviations, summary of adverse events by organ class will be provided in clinical 
phase of CSR. 
15.2 
Archiving 
All data generated in connection with this study, together with a copy of this 
protocol, signed ICDs and the final report will be archived for at least 05 years. 
15.3 
Confidentiality of Data 
The data identifying each subject by name will be kept confidential and will be 
accessible only to the study personnel (involved in check-in procedure) and if 
necessary, to the QA auditors, IEC, sponsor's monitor and Regulatory agency 
(ies). 
Page 66 of83 


Protocol for Drug-Drug 
lnter~Jctioo Study of Spironolactone and Digoxin (Fa.stmg 
Condition) 
Conlidential 
16 
FINANCING AND INSURANCE 
ClinSync has agreement with "United India Insurance company Ltd.," I(Jr the 
insurance coverage of the volunteers pat1icipating in a Bioavailability study. They 
arc covered by "Special Contingency Insurance Policy" for any exigency that may 
happen to them during the study. 
17 
PUBLICATION POLICY 
Publication of results/findings of the study will be at the discretion of the sponsor. 
If published, the subject's identity will not be revealed. 
18 
REFERENCES 
• 
NDA approval letter for Carospir~ (Spironolactone) Oral Suspension, 25 
mg/5 mL, NDA 209478 
• 
Prescription information: Carospir® Spironolactone Oral Suspension, 25 mg/5 
mL manufactured & distributed by CMP Pharma, Inc. 8026 US Highway 
264A, Farmville, NC 27828. 
• 
Prescription infonnation: LANOXIN:;: (digoxin) Tablets, USP 250 meg 
manufactured for Concordia Pharmaceuticals Inc., St. Michael, Barbados 
BBII005. Initial U.S. Approval: 1954; Revised: 12/2016 
• 
USFDA Draft Guidance: Clinical Drug Interaction Studies - Study Design, 
Data Analysis, and Clinical Implications; October 2017 
• 
International Conference on Hannonization; Guidance for Industry, E6 Good 
Clinical Practice: Consolidated Guidance. 
• 
Declaration of Helsinki, 64th WMA General Assembly, Fortaleza, Brazil, 
October 2013. 
• 
Good Clinical Practices For Clinical Research in India- Schedule Y. 
• 
http://who-umc.org/Graphics/24734.pdf 
• 
Guidance for Industry: Statistical Approaches to Establishing Bioequivalence, 
Center for Dmg Evaluation and Research, January 2001 
• 
Guidance for Industry- Bioavailability and Bioequivalence Studies for Orally 
Administered Drug Products - General Considerations I Guidance for Industry 
rVAS/J3ti tN~:·~rrrUTIONAL 
i 
ETHI,,.._.,..,.._,.., rn,v..-,...,..,..1 .,....,-+----------------------------
( 
1
t]~pfif;totjf/E'""'_."P-SPJ-001; Version 02; Date: 07 Aug 2018 
'" -,. ~~~-~--.:.c......;::...==.,J 
Page 67 of83 


; ~~--,: .> .. " ' ; ' 
:: ; . ' l 
i 
: 
' 
Protocol for Drug-Drug Interaction Stud) of Spironolacton-: and Digoxin (Fasting 
Condition) 
C<>nfidcnti:tl 
Conduct and Analysis of Bioavailability and Bioequivalcnce Stud1es (Part A: 
Oral Dosage Formulations Used for Systemic Effects), 
• 
Advicc/Infonnation Request for spironolactone and digoxin IND 120929. 
19 
APPENDICES 
Appendix I 
Schematic Diagram of Study Design 
Appendix II 
Assessment Schedule 
Appendix III Diet Schedule Fonn 
Appendix-IV Laboratory Reference Ranges 
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
Page 68 of83 


Protocol t(lr Drug-Drug Interaction Study of Spironolactone and Digoxm (Fasting 
Condition) 
C\1ntidcntial 
Appendix I: Schematic Diagram of Study Design 
* Bioanalytical method development and validation will be completed before the start of the study 
Protocol No.: C-CMP-SPl-001; Version 02; Date: 07 Aug 2018 
Page 69 of83 


Protocol f(>r Drug-Drug Interaction Study of Spimn,>lactonc and Drgo.xm (Fasting 
Condition) 
Confidential 
Appendix II: Assessment schedule 
The to !lowing time-and-events table illustrates the planned schedule of assessments: 
·Screening ___ __ 
Period I and l1 
'('-28' days 
to day 
'-3') 
Day :nay Day ;nay Day Day Day Day Day :Day Day 
'-1' i I 
:2 
'·3 
14 
5 
6 
· 7 
': 8 
' 9 
iJ 0 
· lntonned consent 
X----------X 
-''--·-·- --
_ _I?C11_10gr_aphy _ 
__ _ _ _:X 
Electrocardio_!,>ra_I11 _______ ~:X __ 
x, 
2D Echocardio.(,>-ram 
X 
. -
• -
;-cilesix-R~.Y· (i>IA"----x---------~------------------~.,---------
-
~ 
! 
~ 
-
-
~-·- ---·-- J 
-
' 
-
i 
---·-,·------! 
view) 
' 
, 
-i31ooctsamPlefor--------~--------· -, ----"'-----"---
x, 
,_!:f~ma!()logL_~-~-
: --~--'--~--~-----j--,-· 
~---. --.---+--_; _____ , ____ _ 
: Blood sample for 
X 
· 
i 
' 
_ 
, 
_ 
: 
· 
: 
· xt 
~~ioci!_emis_tr_y_ _____ -,-__ --'-----,------·--~--' ________ ___; ____ , ____ -------. ---,---: 
' Blood sample for 
serological 
X 
' 
-
' -
: examination 
n:Yrinea!iai)tsis -
x---. -------------------'-----=_ ___ :_.: ___ L_: __ ~--=--'---____ : ____ [__-_i 
, Urine sample for---;·-~-------,--~ 1 _ , _ : _ i _ : _ i _ ! _ ; _ i _ ' _ i 
1 drugs of abuse 
: 
. 
• 
· 
. 
1 
' 
· 
. 
: 
. · 
·Alcohol ~eathtest _: ----=--=x::_c- , ·:--_; ___ ) =:'-:=~, __ ___::..=~-=--- -~ J=.:,;=; 
. Pregnancy test 
: 
-
, X-
-
-
' -
: -
i -
-
-
-
-
, -
: 
--.----------
. 
~---·----~-·-----'-----...........,----..------.-----r--_---------·r--... --~----
, Evaluation of 
; 
, 
: 
I 
' 
i 
' 
: 
' 
1 
' 
I 
1 inclusion/exclusion ! 
X 
; X , -
-
! 
1 -
i - ' -
' 
; criteria3 
1 
i 
/ 
, 
/ 
i 
'Creati;1ine-Ciearafic-eT----·----,--------~. ---------' 
__ 1_1_ 
-,--~---,------T----,
1 
and semm 
· 
X 
-
_ __r_<!t_ass~u_!!l~~v__("L ___ 
' ------1----,--+-------' __ .L __ 
~ --~--------'---L-
C--~ 
! Disp~St!llL 
, 
-
· X 
. X • X • -~--~ ~ _L_:X_L>f.__; X . )(_ ~~-~_: __ 
' Dosing 
-
-
; X5 : xs i X5 ! X5 · X5 , X5 • X5 j X5 1 X' ' -
, 
-------·--·--
-------,----1--------+--~----;-------t··------------------------' 
Urine samples for 
, _ 
_ 
1 
_ 
; X , X . X 
X ' X 
Pharmacokinetics 
_________ :_:.:::_---,-
Blood samples for 
Phannacokinetics 
-------------------
Vital signs 
X 
·measurement ___ \------+ 
Diet schedule 
X 
X 
X 
X 
------,----(··-----:~--~-----+---->-~-----~----] 
X 
X 
X 
X 
x'X 
X 
X 
X,X 
-----' ---- i----1--~----
---···-----~---------,--·-·----------
X 
X 
X 
X 
X 
i 
, 
I 
-Actv~rse'Even!s_____ 
--~-,--~-------T···-~-,-;;--r-~--,~~-··;-_, 
monitoring 
i X , 
, X 
X . X . X : X 
, 
, 
, 
*Chest X-Ray (P/A viC"V.·) \villb~-i3-k"Cll-fO-; the vOfunteer \vhoS~-x:-Ray·~\~as-tai<:en ffiOfe-than 6 -~~10~t'thS ___ _ 
period I. 
-SPI-001; Version 02; Date: 07 Aug 2018 
Page 70 of83 


: _) .. JC 
l'rotllcol f(lr Drug-Drug Interaction Study of Spironolactone and DigclXin (Fasting 
Condition) 
Confidential 
'' ECG will be perfOrmed at 1.00 and 3.00 hours posi do:->t' m each pcnod of the study and befon.> check 
m ofperiod-II & befOre checkout of each period. 
S Spironolactone Oral Suspension will be administered from Day 1 w Day 5 and Day 7 to Day 9. to 
the subj~cts who will be randomized to treatment Bas per randomization scheme and treatment A orB 
\vill be administered on day 6. 
The day prior to drug administrarion in each period for this protocol \Vill be consldc:red as Day '~ 1'. 
The day of dosing in each period for this protocol wiiJ be considered as Day 1. 
1 Post study (hematology and biochemistry) laboratory evaluations \Vill be done at last blood sample 
collection of the study. 
1 Semm pregnancy test will be done for female subjects with child bearing potential and Urine 
pregnancy test will be done for post-menopausal female subjects during screening, each period 
check-in (Day'-!'). 
3 Evaluation of inclusiontexclusion criteria will be carried out prior to check-in of period 1 of the 
study. 
4 Investigational products (substrate) \Viii be dispensed a day before dosing and perpetrator \V'ill be 
dispensed on the day of dosing in each period of the study. 
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
Page 71 of83 


Protocol for Drug-Drug Interaction Studv nf Spironolactone and Digoxin {Fasting 
Condition) 
Contidential 
Appendix Ill: Diet Schedule Form 
Dav 01 
··--,-
I 
Name Of Cooked Food 
Wt. In 
Proteins 
Carbohydrates 
Fats (g) 
K.Cal -1 
Dinner 
Plain Rice 
Pulka (I) 
(Dav -Oil 
Red Gram Dhal 
Ladies Finger Curry 
Chutney 
Sarnbar 
Curd 
I 
Papad (I) 
Breakfast 
0.50 hour 
Puri 
after dosing 
Potato Curry 
Plain Rice 
Pulka (I) 
/!&!!s!! 
Red Gram Dhal 
04.00 hour 
Capsicum Curry 
after dosing 
Chutney 
Sam bar 
Curd 
Papad (I) 
Snacks 
08.00 hour 
Onion Pakori 
after dosing 
Plain Rice 
Pulka (I) 
Red Gram Dhal 
Egv Currv 
I Dinner 
Chutney 
1 12.00 At least 
Sambar 
I 0 hours before 
Curd 
dosing 
Papad (!) 
Total 
L 
{VASA VI INSTITUTIONAl 
f 
ETHICS CO!vil\-iiTTEE 
··-.,~"?l'SD 
I 
I 
I 
! 
I 
I ' 
(g) 
(g) 
(g) 
500 I 
II 
125 
35 
03 
17.5 
100 __J___j .4 
12.5 
100 
3.5 
13 
30 
0.3 
1.3 
150 
3.7 
i 
II 
100 
3.1 
3.0 
10 
1.2 
0.8 
75 
I 
6.1 
I 
35.0 
100 
1.5 
I 
16.0 
500 
' 
II 
I 
125 
35 
03 
1 
17.5 
100 
4.4 
12.5 
100 
1.00 
12.00 
30 
0.3 
l 
L3 
100 
2.5 
7 
100 
3.1 
3.0 
10 
1.2 
0.8 
60 
I 
6.6 
I 
25.0 
500 
II 
125 
35 
03 
j_ 
17.5 
100 
4.4 
! 
12.5 
100 
6.0 
7.0 
30 
0.3 
1.3 
100 
2.5 
7 
100 
3.1 
3.0 
10 
1.2 
0.8 
Protocol No.: C-CMP-SPJ-001; Version 02; Date: 07 Aug 2018 
0.75 
550.75 I 
0.45 
I 
86 05 
-·-------, 
I 
1.4 
I 
80.20 
' 
! 
6.0 
120.00 
-
1.6 
20.80 
-
3.5 
90.30 
4.0 
60.40 
1.5 
21.50 
Total= 1030.00 
I 
I 
8.4 
I 240.00 
I 
6.0 
I 124.00 
Total =364.00 
0.75 
I 550.75 
0.45 
86.05 
' 
1.4 
80.20 
6.00 
106.00 
1.6 
20.80 
2.5 
60.50 
4.0 
60.40 
1.5 
21.50 
' 
Total= 986.20 
I 
12.8 
I_ 241.60 
Total= 241.60 
0.75 
550.75 
0.45 
86.05 
1.4 
80.20 
7.0 
!15.00 
1.6 
20.80 
2.5 
60.50 
4.0 
I 
60.40 
' 
1.5 
21.50 
,_ 
995.20 
Grand Total= 2587.00 
Page 72 of83 


' I 
i 
Pro!I.Jcol for Drug-Drug interaction Study of Spin)nolactonc omd Digoxin (Fasting 
Condition) 
Day 02 
J 
Nan:: Of Cooked Food 
\Yt. In ~~~~teins 1 
(g) 
' 
(u) 
i 
i 
~ 
Conlicknt ial 
Carboh)'dralesl-~~~T~----.-,j. 
(u) 
I(~ 
b 
h 
-
I 
Idlv(4) 
I 
160 I 6c2 __ 
Breakfast 
45.5 
OA 
211.6 
0.50 hour 
r--~-----
2.5 I 
60.50 
Sambar 
, ___ J ___ I 00 
___ :].0_ __ 
7 
after dosing 
Chutney (Coconut) ! -S()j-
3.0 
I 
Plain Rice 
Pulka (I) 
Red Gram Dhal 
Cluster beans curry 
M!!!£h 
Chutney 
04.00 hour 
Sam bar 
after dosing 
Curd 
Papad (I) 
Samosa (I) 
~ 
08.00 hour 
Plain Rice 
after dosing 
Pulka (I) 
Red Gram Dhal 
Ridge Gourd curry 
Chutnev 
Tomato Rasam 
Curd 
Dinner 
Papad (I) 
12.00 At least I 0 
hours before dosing 
VASAVIINSTITUTIONAl 
ETHICS COMMITTEE 
APPfjJJVED 
i 
I 
500 
II 
35 
I 
03 
100 
' 
4.4 
125 
4.0 
30 
0.3 
100 
2.5 
100 
3.1 
!0 
1.2 
65 
I 
2.5 
500 
II 
35 
03 
100 
4.4 
100 
1.0 
30 
i 
0.3 
100 
1.0 
100 
3.1 
10 
1.2 
9.0 
125 
!7.5 
12.5 
10.0 
1.3 
7 
! 
3.0 
o.x 
I 
21 
125 
17.5 
12.5 
4.0 
1.3 
4.0 
3.0 
0.8 
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 20!8 
' 
15 J 
I 79.00 
Total- 451.10 
0.75 
550.75 
i 0.455 
86.05 
1.4 
80.20 
6.0 I 
1 10.00 
1.6 
20.80 
2.5 
60.50 
4.0 
60.40 
1.5 
21.50 
Total ~ 990.20 
12.s I 
206.50 
I o.75 
550.75 
0.45 
86.05 
1.4 
80.20 
5.0 
65.00 
1.6 
20.80 
2.0 
38.00 
4.0 
60.40 
1.5 
21.50 
Total- 922.70 ' 
Grand Total~ 2570.50 
Page 73 of83 


Protocol for Drug-Drug interaction Stud)' of Spironolactone and Digoxin (Fasting 
Condition) 
Contidentwl 
Day 03 
~----- Name Of Cooked Food 
iroteins ] 
----
\\'t. In 
Carbohydrate~ K.Cal 
(g) 
(g) 
I 
(g) 
(g) 
Breakfast 
[ Vada (4) 
__ ___,_ 
88 
10.5 
30 
11.5 . 265.50 
0.50 hour 
Sambar 
I 
75 
1.75 
l 
4.75 
2.00 
44.00 
' 
after dosing 
Chutney (Coconut) 
80 I 
3.00 I 
9.00 
15.0 
l79:oo 
I 
-
Total - 488.50 
i 
11mh 
Plain Rice 
I 500 
J I 
125 
0.75 
550.75 
1 
Pulka(l) 
' 
35 
I 
03 
17.5 
0.455 
86.05 _j 
Red Gram Dhal 
100 
4.4 
12.5 
1.4 
80.20 
Nutrella curry 
100 
5.00 
10.0 
i 6.00 
114.00 
04.00 hour 
Chutney 
30 
0.3 
l.3 
I 1.6 
20.80 
after dosing 
Sambar 
100 
2.5 
7 
I 2.5 
60.50 
Curd 
100 
I 
3.1 
3.0 
I 4.0 
60.40 
Papad (l) 
' 
10 
L2 
0.8 
I 
1.5 
21.50 
___)_ 
Total= 994.20 
Masala Vada (Gare) 
60 
6.5 
I 
20.0 
I 7.0 
169.00 
' 
~ 
Total= 169.00 
08.00 hour 
Plain Rice 
500 
II 
125 
0.75 
550.75 
after dosing 
Pulka(l) 
35 
03 
17.5 
0.45 
86.05 
Red Gram Dhal 
100 
4.4 
12.5 
1.4 
80.20 
Brinzal Curry 
100 
1.00 
4.00 
5.00 
65.00 
' 
Chutney 
30 
0.3 
L3 
1.6 
20.80 
Tomato Rasam 
100 
1.0 
4.0 
2.0 
38.00 
Dinner 
Curd 
100 
3.1 
3.0 
4.0 
60.40 
12.00 At least I 0 
Papad (I) 
10 
1.2 
0.8 
1.5 
21.50 
hours before dosing 
Total - 922.70 
Grand Total= 2574.40 
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
Page 74 of83 


Protocol for Drug-Drug Interaction Study of Spnonolacwnc and Digoxm (Fasting 
Condition) 
Day 04 
-------- ------------r-· 
j \Vt In 
1\"ame Of Cooked Food 
reakfast 
50 hour 
at 1er dosing 
mch 
.00 hours 
ter dosing 
acks 
.00 hours 
~ 
08 
aft er dosing 
ner 
Din 
12. 
hou 
00 At least 10 
rs befOre dosing 
I 
L_ 
' 
yennicclli Upma 
Tomato Chutney 
Plain Rice 
-~~lka(l) 
Red Gram Dhal 
Kovi (Donda) curry 
Chutney 
Sambar 
Curd 
Papad (I) 
Sandwiches (2) 
Plain Rice 
Pu1ka(1) 
Red Gram Dha1 
Masa1a Brinza1 
Chutnev 
Tomato Rasam 
Curd 
Papad(l) 
I VASA VI INSTITUTIONAL 
I 
ETHICS COMMITTEE 
/APPROVED 
' 
(g) 
(g) 
- 240--r-s7 
60 
0.6 
500 
II 
35 
f 
03 
100 
4.4 
100 
1.6 
30 
0.3 
i 
100 
2.5 
I 
100 
3.1 
I 
10 
1.2 
65 
3.2 
500 
ll 
35 
03 
100 
4.4 
100 
3.0 
30 
0.3 
100 
1.0 
100 
3.1 
10 
1.2 
' 
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
Conlidcntial 
' 
' K.Cal 
(g) 
! 
(g) 
63.0 
12.00 
390.0 
2.6 
3.2 I 41.60 
Total~ 431.60 
125 
I 0.75 
550.75 
17.5 
0.455 
86.05 
12.5 
1.4 
soc~ 
6.0 
' 5.6 
78.00 
' 
1.3 
1.6 
20.80 
7 
2.5 
60.50 
3.0 
4.0 
60.40 
0.8 
1.5 
2150 ' 
Total= 958.20 
14.0 
14.1 
194.00 
Total ~ 194.00 
125 
I o.75 
550.75 
!7.5 
0.45 
86.05 
!?.5 
1.4 
80.20 
7.0 
10.0 
130.0 
J.3 
1.6 
20.80 
4.0 
2.0 
38.00 
3.0 
4.0 
60.40 
0.8 
1.5 
21.50 
Total~ 987.70 
Grand Total~ 2571.50 
Page 75 of83 


>' :' \ 
I 
Protocol ior Drug-Drug lntcmcrion Study of Spironolactone and Dq,;uxin (Fasting 
Condition) 
Confidential 
Day 05 
~-
--
Wt. In Trroteins j Carbohydrates . --·r-----
' 
Name Of Cooked Food 
!oats I K C I 
I 
( ) 
. a 
{g) 
! 
(g) i 
(g) 
' 
J Breakfast 
Masala Dosa 
I 00 J 3.8 ~ 
' 0.50 hour 
' after dosing 
Chutney (Coconut) __ l_ __ ~_j _ ___:J_2_0 
. ---
Plain Rice 
Pulka( l) 
Red Gram Dhal 
!:.Y.!!£h 
Mixed Veg curry 
04.00 hours 
after dosing 
1 Chutney 
Sambar 
Curd 
Papad (l) 
I 
I 
Snacks 
Double ka Meetha 
08.00 hours 
after dosing 
Plain Rice 
Pulka(l) 
Red Gram Dhal 
Ladies Finaer Curry 
Dinner 
Chutney 
12.00 
Tomato Rasam 
At least 10 hours 
Curd 
before dosing 
Papad (I) 
I 
VASAVIINSTiTUTIONAL 
ETHiCS CO\H\.11TfEE 
APPROVED 
-·------"-1 
I 
I 
I 500 I 
ll 
I 
i 
35 
03 
100 
4.4 
100 ' 
5.0 
I 
30 
0.3 
100 
2.5 
100 
3.1 
10 
1.2 
105 
4.1 I 
I 
500 
11 
35 
03 
100 
4.4 
100 
3.5 
30 
0.3 
100 
1.0 
100 
3.1 
10 
1.2 
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
g 
I 
30 
I 
6.5 
I 192.00 
-- ']so I 
9.00 
179.00 
Total- 371.00 I 
I 
125 
I 0.75 
550.75 
17.5 
.I 0.455 
86.05 
12.5 
1.4 
80.20 
13 
I 6.0 
126.00 
L3 
1.6 
' 20.80 
7 
2.5 
60.50 
3.0 
4.0 
60.40 
0.8 
1.5 
21.50 
Total = I 006.20 
24 
I 17.7 
276.00 
Total = 276.00 
125 
0.75 
550.75 
17.5 
0.45 
86.05 
12.5 
1.4 
80.20 
13 
6.0 
120.00 
1.3 
1.6 
20.80 
4.0 
2.0 
38.00 
3.0 
4.0 
i 60.40 
0.8 
1.5 I 21.50 
Total- 977.70 
.•. 
Grand Total= 2630.90 
Page 76 of83 


Protocol f[w Drug-Drug Interaction Study of Spmmolactonc and Drgoxin (Fasting 
Condition) 
Day 06 
Name Of Cooked Food 
I 
' 
j Lunch 
\ Plain Rice 
' 04.00 hours 1 Pulka(l) 
after dosmg 
Red Gram Dhal 
Potato Curry 
Chutney 
, Sambar 
Curd 
Papad (1) 
Snacks 
Milk with I Og sugar 
08.00 hours 
after dosing 
Bread 
Plain Rice 
lli.!lli£! 
Pulka(1) 
12.00 hours 
RedGmmDhal 
after dosing 
Brinzal Curry 
Chutney 
Sambar 
Curd 
I 
Papad (1) 
I 
VASA Vi INSTITUTIONAL 
ETHICS COiV!MITTEE 
l LAPPltQVED 
500 
I 
35 
·+ 
100 
100 
30 
150 
100 
10 
200m! 
40 
I 
I 500 
i 
35 
100 
100 
30 
150 
i 
100 
10 
I 
Proteins 
(g) 
II 
03 
4.4 
Carboh_ydratcs 
(g) 
125 
17.5 
12.5 
1.5 
' 
16 
·-·--+-
1.3 
0.3 
3.7 
11 
3.1 
3.0 
1.2 
' 
0.8 
7.0 
20.0 
3.8 
25.8 
II 
125 
03 
17.5 
4.4 
12.5 
1.00 
4.00 
0.3 
!.3 
3.7 
II 
3.1 
3.0 
1.2 
I 
0.8 
I 
I 
Fats 
(g) 
0.75 
0.455 
1.4 
6.0 
1.6 
3.5 
4.0 
1.5 
Confidential 
K.Cal 
550.75 
86.05 
80.20 
124.00 
20.80 
90.30 
60.40 
21.50 
Total~ 1034.00 
6.0 
162.00 
1 0.9 
126.50 
Total ~ 288.50 
0.75 
550.75 
0.45 
86.05 
1.4 
80.20 
5.00 
65.00 
!.6 
20.80 
3.5 
90.30 
4.0 
60.40 
1.5 
2!.50 
Total- 975.00 
Grand Total= 2297.50 
-
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
Page 77 of83 


' 
I I 
ProtOCl)l for Drug-Drug lntt.:rJdion Study of SplrOJWlactone <.md Digl)xin (Fasting 
Condition) 
Confidential 
Day 07 
~-------------·..,----....... 1---....... -------.--..,-----, 
.N •nte Of Cooked Food 
K Cal 
\Vt·. In 
Proteins 
Carboh~·drales 
Fats 
~· 
1-o:----:-:--:--
.. --r--;-;-;--;--;c:-----T-'"7(7-g);-L (g) 
(g) 
(g) 
• 
. • 
Breakfast 
~Jv(4) -~--·~ ___ 
16_0 __ J. ... __ 
6.,_· _______ 4_5,5 ____ 0.4 1 ... :2.!.!.:~-....j 
0.50 hour 
i-"S"'aic:Do:h•o::r......,.=----c_j-..C!O"CO'--+I-...:2c:.·'o:.. -·+ 
7 
I 2 5 I 
60_~ 
atior dosing 
Chutney (Coconut) 
80 
3.0 
9.0 
. 
15 I 179.00 
Total= 451.10 
Plain Rice 
1-- 500 
11 
125 
0.75 
550.75 
Lunch 
Pu1ka(l) 
35 
03 
I 
17.5 
0.455 
86.05 
04.00 hours 
I Red Gram Dha1 -+ 
. 
' 
100 
4.4 
12.5 
1.4 
80.20 
' 
after dosing 
I Tomato Methi Curry 
100 
5.00 
10.0 
5.00 
68.00 
Chutney 
30 
0.3 
1.3 
1.6 
20.80 
Sambar 
100 
2.5 
7 
2.5 
60.50 
Curd 
100 
3.1 
3.0 
40 
60.40 
Paoad (I) 
10 
1.2 
0.8 
1.5 
I 21.50 
~ 
Total = 948.20 
08.00 hours 
Masa1a Vada (Gare) I 
60 
! 
6.5 
I 
20.0 
7.0 i 169.00 
after dosing 
I 
Total= 169.00 
Plain Rice 
500 
I 
11 
125 
0.75 
550.75 
Pu1ka(l) 
35 
03 
17.5 
0.45 
86.05 
lli!!!!f!: 
Red Gram Dhal 
100 
4.4 
12.5 
1.4 
80.20 
12.00 hours 
Egg Curry 
100 
I 
6.0 
7.0 
7.0 
115.00 
after dosing 
Chutney 
30 
0.3 
1.3 
1.6 
20.80 
··-
· Sambar 
100 
2.5 
7 
2.5 
60.50 
Curd 
100 
3.1 
3.0 
4.0 
60.40 
Papad (I) 
10 
1.2 
0.8 
1.5 
21.50 
Total = 995.20 
Grand Total = 2563.50 J 
VASAV! INSTITUTIONAL 
I tTHICS CONv11TIEE 
!APPROVED 
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
Page 78 of83 


I i 
'- ,' : 
Protocol fix Drug-Drug Interaction Study of Spironolactone and Digoxin (F;btlllg 
Condition) 
ConJi,kntial 
Day 08 
~:~~;~~~-~~;~~-~~~ 
~;;• T K.Ca~-~ 
1 8s ~ 
w.s 
~~--____l()· 
. 11 T'26sJDj 
1 
7s 
!.75 
__ _i_ZoL...........J. 2.oo 
44.oo . 
j 
NamC' Of Cooked Jiood 
hJ;:;,akfast 
Vada (4) 
0.50 hour 
Sambar 
after dosing 
Chutney (Coconut) 
' 
so 
3.oo 
1 
9.oo___ I 15.0 
179.00 I 
II Lunch 
04.00 hours 
! after dosing 
I 
I 
Snacks 
08.00 hours 
after dosing 
~ 
12.00 hours 
after dosing 
Total-488~ 
~--;;-P,.-Ia7
in...,Ri""·-ce---·--,--:c5o'-:o:--•-·---:l-:--t--,...-
12s 
o.7s 
s5o.7SI 
Pulka(l) 
35 
03 
17.5 
0.455 
86.05 
I 
~R"'ect"'a"'r"'a'-m--;D,;:I;-->a-;1 ---t-7:1 o"'o:--+---:4."=4-+ 
! 2.5 
1.4 
80.20 I 
Beans curry 
100 
4.0 
08 
5.0 
93.00 
ChutneY 
30 
0.3 
1.3 
1.6 
20.80 
Sambar 
100 
2.5 
7 
2.5 
60.50 
Curd 
100 
3.1 
3.0 
4.0 
60.40 
Papad (I) 
10 
1.2 
0.8 
1.5 
21.50 
Total ~ 973.20 
• Punttgvlu 
I 
60 
! 
4.5 
I 
16 0 
! 8.0 
' !54.00 
Tomato Chutney 
I 
60 
I 
o.6 
I 
2.6 
3.2 I 41.60 
Total ~ 195.60 
Plain Rice 
500 
I I 
125 
0.75 
550.75 
Pulka(l) 
35 
03 
17.5 
0.45 
86.05 
Red Gram Dhal 
100 
4.4 
12.5 
1.4 
80.20 
Capsicum Curry 
100 
1.00 
12.00 
6.00 
106.00 
Chutney 
30 
0.3 
1.3 
1.6 
20.80 
Tomato Rasam 
100 
1.0 
4.0 
2.0 
38.00 
Curd 
100 
3.1 
3.0 
4.0 
60.40 
Papad (I) 
!0 
1.2 
0.8 
I 1.5 
21.50 
Total- 963.70 
Grand Total= 2621.00 
'I VASAV! '.NST. ITUTIONAL 
, 
ETHICS CC¥MITTEE 
lAPPROVED 
Protocol No.: C-CMP-SPI-00 1; Version 02; Date: 07 Aug 2018 
Page 79 of83 


Protocol for Drug-Drug lntemction Study of Spironolactone and Drgoxin (Fasting 
Condttion) 
Confidential 
Day 09 
Total= 329.50 
Plain Rice 
500 
II 
125 
0.75 
550.75 
Lunch 
Pulka(l) 
35 
03 
17.5 
0.45 
86.05 
1 
04.00 hours 
1 Red Gram Dhal 
100 
4.4 
12.5 
1.4 
80.20 
after dosing 
3.0 
Carrot Peas cuny 
100 
10.0 
6.0 
106.00 
I 
Chutney 
30 
0.3 
1.3 
1.6 
20.80 
I 
Sambar 
100 
2.5 
7 
2.5 
60.50 
Curd 
100 
3.1 
3.0 
' 
4.0 
60.40 
I 
Papad(l) 
10 
1.2 
0.8 
I 1.5 
21.50 
I 
Total = 986.20 
' 
1 Snacks 
. 
08.00 hours 
Samosa(I) 
65 
2.5 
21.0 
12.5 
206.50 
after dosing 
Total= 206.50 
Veg pu!avo 
600 
14 
I 14 
15 
647.00 
Mirch ka 
190 
3 
18 
15.4 
222.60 
Dinner 
Salan(Capsicum) 
12.00 hours 
after dosing 
Sambar 
100 
2.5 
7 
2.2 
60.50 
Curd 
]1)0 
3.1 
3.0 
4.0 
60.40 
Total = 990.50 
Grand Total= 2512.70 I 
Note: 1 g PROT!EN = 4 K.Cal; l g CHO = 4 K.Cal; lg FAT= 9 K.Cal 
References: Nutritive Value ofindian Foods by Gopalan et.al, N!N, Count What 
You Eat by Swarm1 Pas1icha, NIN and Food Composition Table of Indian foods 
2017, NIN. 
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
Page 80 of83 
' 


PrL)tocol fln Drug-Drug Interaction Study of Spironolactone and Digoxin (Fasting 
Condition) 
Confidential 
Appcndix-IV: Laboratory Reference Ranges 
r-· 
PARAM~TER ___ ] 
___ ~~BORATORY REFERENCE RANGES 
r
~ ---------------------,H_E_~fATOLOGY 
Male:l3-l8 g/dL 
Hemoglobin 
Female:ll5-l6 g/dL 
WBC Count 
4000- 11000 Cell/cumm 
RBC Count 
4.5- 5.5 mill;d 
I 
Platelet Count 
1.50-4.50 lakhs/cumm 
I 
Neutrophils 
40-75% 
I 
Lymphocytes 
20-40% 
Eosinophils 
01-06% 
Monocytes 
02-10% 
Basophils 
00-0 I % 
IL----------!--------------1 
ESR 
0-15 mm/hr 
.. 
CLINICAL BIOCHEMISTRY 
Bilirubin Total 
<1.0 mg/dL 
Bilirubin Direct 
<0.3 mg/dL 
Alkaline Phosphatase 
50-136 U/L 
I 
1------+------------------11 
AST!SGOT 
15-37 U!L 
. 
ALT!SGPT 
30-65 U!L 
~-----------------------~1-----------------------------------~ 
Protein Total 
_ 
6.4-8.2 g/dL 
Albumm 
3 4-5 0 gldL 
~----------------------~--------------------------------~ 
r;,;::;-;::b,-;;:-;;:=:;-;:::-=:-:1'-!.l' Ji' a 
I 0-5 0 mg/ dL 
! VAS VIINSTITI '101\16.1 
i ETH._::., ::·.~· "'"··:. 'C_E: 
!APf:tKl)\fEiJ .1P-SPI-001; Version 02: Date: 07 Aug 2018 
.. ---·~ 
... :._::c...=:::::..~ 
Page 81 of83 


Protocol f{n Drug-Drug Interaction Study of Spironolact~)JlC and Digoxin (Fasting 
Condition) 
Contldcnlial 
' 
-
-
I 
Glucose Random 
' 
70-!30 mgidL 
I 
I 
I 
___j 
I 
I 
Total Cholesterol 
<200 mg/dL 
I 
__j 
Creatinine clearance 
80-120 ml/min 
I 
____, 
Sodium 
135-145 nunol/L 
I 
-
' 
3.5-5.5 mmol!L 
I 
Potassium 
I 
Chloride 
94-108 mmol!L 
I 
Calcium 
8.5-10.1 mgldL 
. 
. 
CLINICAL PATHOLOGY 
Reaction (pH) 
5.0-8.0 
Specific Gravity 
1.000-1.030 
I 
Proteins 
Nil 
Glucose 
Nil 
Ketones 
I 
Negative 
Bilirubin 
Negative 
' 
Blood 
I 
Negative 
Urobilinogen 
Normal 
PUS Cells {WBC) 
I 
0-SIHPF 
I 
I 
UrineRBC 
Nil 
i 
U .Epithelial Cells 
I 
0-SIHPF 
I 
I 
-~ 
1 VASAVIINSTITU 1 
P-SPl-001; Version 02; Date: 07 Aug2018 
Page 82 of83 


.-, ---' '--\ 
,,; y : j 
Protocol f{)r Drug-Drug Interaction Stud_y of Spironolactone and Digoxin (Fasting 
Condition) 
Con fidcnti al 
I 
PARAMETER--~--ILA.BORA:~~~-~-y RE~ERENCE RA~GES~·l 
r 
I 
. 
I --··-··C~~~~Crystals 
·1-----·---~- --~-- ~-l 
I
~ 
11\fMUNOL_O_G_\_'IS_E_'R_O_L_O_G_\_' ------------{ 
Hepatt!Is B Surface Antigen 
<I .0-Negative 
I 
(HbsAg) 
-~ 
>1.0-Positive 
___ J 
Hepatitis C Virus (HCV) 
HIV 1 & 2 Antibody 
<1.0-Negative 
>I .0-Positive 
<1.0-Negative 
> 1.0-Positive 
/ 
VORL 
l :8 & Above Significant 
J 
Note: Referral diagnostiC ranges will be considered for the parameters which are not covered in 
the above table. 
fVASAV! IN~HTUTIONAL 
j 
ETHiCS COMMiTTEE 
lAPP ROVED 
Protocol No.: C-CMP-SPI-001; Version 02; Date: 07 Aug 2018 
Page 83 of83 


(' (,\. 
\.... 
. 'y ) 
PROTOCOL AMENDMENT 
Protocol No.: C-CMP-SPI-001 
Protocol Title: An open label. balanced, randomized. single-dose. two-treatment. two-sequence, 
1\\o-period. crossover oral drug-drug interaction study of spironolactone (perpetrator) and 
Digoxin (substrate drug) in healthy adult human subjects under tasting condition. 
Protocol No.: C-CI\.11'-SPI-001: Version:O I; Date: 13 Feb 20 18; Version:02; Date: 07 Aug 20 18; 
Amendment No.: 0 l: Date: 19 Dec 2018: 
I Section 
! 
Changed to present statement in 
Present statement in Protocol 
1 j 
Protocol 
Reason 
CRO & Clinical Study site 
I 
Protocol title 
CRO & Clinical Study site 
ClinSync Clinical Research Pvt. 
Ltd. 
ClinSync Clinical Research Pvt. Ltd. 
JSR Mall, Plot No.7 to !8, Madinaguda 
~~ 
I 
page 
#4-1-1, Hayathnagar, 
Hyderabad, Telangana- 501505, 
India. 
Principal Investigator 
Dr. Roopali K. Somani, 
I 
Village, Seri!ingampally Mandai, 
Hyderabad-500050, 
Telangana, India. 
Principal Jn\'estigator 
Dr. P. Venkatesh, MBBS, Ph.D 
MD Pharmacology 
Clinical Pharmacology Department, 
Clinical Pharmacology Department, 
ClinSync Clinical Research p,i. Ltd., 
ClinSync Clinical Research Pvt. 
JSR Mall, Plot No.7 to 18, Madinaguda 
Ltd., #4-I -I. Hayathnagar, 
Hyderabad, Telangana- 501505, 
India. 
Phone No.: +91-40-2420300 I /2/3 
Village, Serilingampally Mandai, 
I 
Hyderabad-500050, 
. Telangana, India. 
Section 1: 
Fax No.: +91-40-24203000 
Phone No.: +9 I -40-24203001/2/3 
Fax No.: +91-40-24203000 
I Study I 
Email ID: roopali.somam@clmsyn · Email JD: venkatesh.p@clmsynccro.com I 
I. Information f-c::oc_r;-o-;.c_o_m_. -c:---:---------t-;;--;-;;----:-::---:------------1 
Sub Inwstigator 
Sub Im·estigator 
Dr. Sagar Chandra S B huyar, 
' Dr. Sagar Chandra S Bhuyar, 
MD General Medicine, 
MD General Medicine, 
DNB (cardiology) 
DNB (cardiology) 
Administrative 
change 
25007A-01 
Page I of7 


;"' ,' 
~, 
/':\' 
\,.-
'vi 
PROTOCOL AMENDMEI'I;T 
~----~
1
1 ClinSync Clinicarl(e~carch Pvt . Ud.l ClinSyn~·.Ciinic,;-IRe~carcllPvr Ltd .. --~ 
[ 
#4- I- I, Hayatllnagar, Hyderabad, ! JSR Mall. Plot No.7 to 18, Madinaguda I 
I 
llelangana- 501505. India. 
I Village, Serilingampa!ly Mandai. 
I 
I 
25007A-01 
I 
Phone No.: +91-40-24203001/2/3 
Hyderabad-500050, 
1 
Fax No.: +91-40-24203000 
Telangana, India. 
Phone No.: +9!-40-2420300!/2/3 
Clinical Investigator's 
Dr. Chandra Prakash Vijaya Ram, 
MBBS 
Clinical PhamJacolOh'Y Department, 
ClinSync Clinical Research Pvt. 
Ltd., 
#4-l-1, Hayathnagar, Hyderabad, 
Telangana- 501505, India. 
Phone No.: +91 -40-2420300 l/2/3 
Fax No.: +91-40-24203000 
EmaillD: 
cp.researchscientist@clinsynccro.c 
om 
Dr. Yani Malisetti, MD OBG 
Clinical Phannacology Department, 
ClinS)"lC Clinical Research Pvt 
. Ltd., 
#4-I -l, Hayathnagar, Hyderabad, 
Telangana- 50!505, India. 
Phone No.: +9l-40-2420300l/2/3 
Fax No.: +9\-40-24203000 
Email ID: 
vani.mal isetti @cl ins ynccro. com 
Dr. Polepally Praveen Kumar. 
ETH:cs 
rEt 
Fax No.: +9!-40-242030::10 
. 
. Clinical Investigator 
Dr. Chandra Prakash Vijaya Ram, 
MBBS 
Clinical Pharmacology Department, 
ClinSync Clinical Research Pvt Ltd., 
JSR Mall, Plot No.7 to 18, Madinaguda 
Village, Serilingampally Mandai, 
Hyderabad-500050. 
Telangana, India. 
Phone No.: +91-40-24203001/2/3 
Fax No.: +91-40-24203000 
EmaiiiD: 
cp.researchscientist@clinsynccro.com 
Page 2 of7 
I 


f' 
' 
(v 0 \ 
c 
I 
I 
I 
25007A-O I 
" 
:\ 
.. < 
PROTOCOL AMENOMENT 
<c-=-::"7·---------------
i MBBS 
) Clinical Pharmacology DepartmL"nt 
I 
j ClinSync Clinical Research Pvt. Ltd. 
#4-1-1. Hayathnagar, Hyderabad, 
Telangana- 501505, India. 
I Phone No.: +91-40- 2420300 I /2/3 
Fax No.: +91-40-24203000 
Emaii!D: polepally.praveenkumar 
@ clins)'llCcro.com 
Bioanalytical Investigator 
Bioanalyticallm·estigator 
Mr. Chirag Khatri, M. Sc., 
Mr. Chi rag Khatri, M. Sc., 
ClinSync Clinical Research Pvt. Ltd.J ClinSync Clinical Research Pvt. Ltd., 
#4-1-1, Hayathnagar, Hyderabad, 
JSR Mall, Plot No.7 to 18, Madinaguda 
Telangana- 501505, India. 
Village, Serilingampally Mandai, 
Phone No.: +91--40 24203001/2/3; 
Hyderabad-500050, 
Ext: 400 
Telangana, India. 
Fax No.: +91--40-24203000 
Phone No.: +91--40-2420300 1/2/3; 
Email JD: 
Ext: 417 
- chirag.khatri@clinsynccro.com 
Fax No.: +91-40-24203000. 
/ Email ID: 
I 
chirag.khatri@cl insynccro.com 
PK Investigator 
I PK Investigator 
Dr. Jaganmohan S, M.Phann, Ph. D, Dr. Jaganmohan S, M.Phann, Ph.D, 
PDF 
PDF 
PK, BS and MW Department, 
PK, BS and MW Department, 
ClinSync Clinical Research Pvt. Ltd. ClinSync Clinical Research Pvt. Ltd., 
I #4-1-1, Hayathnagar, Hyderabad, I 
JSR Mall, Plot No.7 to !8, Madinaguda 
I 
Telangana- 501505, India. 
I Village, Serilingampa!ly Manda!, 
Phone No.: +91-40-2420300 11213; 
Hyderabad-500050, 
I 
. 
Ext: 604 
I Telangana, Jnd1a. 
Fax No.: +91-40-24203000 
Phone No.: +91-40-2420300 I /2/3; 
t·, '.-'l --~T ~·nrnor'.!.4L 
.;;-::· ( < • ,.-i\,iiTTEF 
Page 3 of 7 


25007A-01 
PROTOCOL AMENDMENT 
! EmaiiJQ-------------~ht: 301 
/ jaganmohan.somagoni![fclinsynccr I fax No.: -i-91~-10<24203000 
j o.com. 
I Email ID: 
J 
I jaganmohan.somagoni(?clinsynccro.co 
111. 
~--~~--~-------r-~~---~---------· 
Statisticalln\'estigator 
I Statisticallnwstigator 
Mr. Tushar Dilip Shinde, M. Sc 
/ Mr. Tushar Dilip Shinde, M. Sc 
BS Depa11ment, 
I 
BS Department. 
ClinSync Clinical Research Pvt. Ltd.j ClinSync Clinical Research Pvt. Ltd., 
#4-1-1, Hayathnagar, Hyderabad, I 
JSR Mall, Plot No.7 to 18, Madinaguda 
Telangana- 501505, India. 
Village, Selilingampally Mandai, 
Phone No.: +91-40-24203001/2/3; 
Hyderabad-500050, 
Ext: 604 
Fax No.: +91-40-24203000 
Emaii!D: 
tushar.shinde@clinsynccro.com 
Telangana,lndia. 
Phone No.: +91-40-24203001/2/3; Ext: 
1301 
I 
Fax No.: +91-40-24203000 
EmaiiiD: 
:ushar.shinde@clinsynccro.com 
I Clinical Facility and Screening 
Facility 
Clinical 
Facility 
and 
Screening 
Facility 
ClinSync Clinical Research Pvt. Ltd. ClinSync Clinical Research Pvt. Ltd. 
Clinical Pharmacology Depa11mem, 
#4-1-1, Hayathnagar, Hyderabad, 
Telangana- 501505, India. 
Phone no.: +91-40- 2420300 I /2/3 
Fax no.: +91-40-24203000. 
Clinical Pharmacology Depa111nent, 
JSR Mall, Plot No.7 to 18, Madinaguda 
Village, Serilingampally Manda!, 
Hyderabad-500050, 
Telangana, India. 
Phone no.: +91-40-2420300 11213 
Fax no.: +91-40-24203000. 
Page 4 of? 


PROTOCOL AMEi\D!\1ENT 
~----r---··-····· . 
···-···--···-r-=c·-------~-------------~--------· -, 
I 
1 Bioanalytical,l' "Bioan:tlytical, 
j 
, 
I 
I 
) 
! Pharmacokhu:fic and Statistical 
I' PJu1rmac..·okinetic and Statistical 
! 
! 
' 
' 
• 
/ Facility 
! Facility 
l 
II 
j ClinSync Clinical Research Pvt Ltd.
1
i ClinSync Clinical Research Pvc Ltd. 
[ 
I 
#4- I -I. Hayathnagar. Hyderabad, 
Clinical Pharmacology Depalilllent, I 
, Telangana- 50 I 505, India. 
I 
JSR Mall, Plot No.7 to I 8. Madinaguda I 
I Phone no.: +9 I -40- 2420300 I /2/3 
Village. Serilingampally Mandai, 
f Fax no.: +9 I -40-24203000. 
Hyderabad-500050, 
1
1 
Telanf'"ana. India. 
X-Ray Facility 
SUNRISE HOSPJT ALS 
H. #: 4-9-32 I, Plot# 4 & 7, 
Hayathnagar, R.R. Dist, 
Hyderabad-50 1505. 
Phone no.: 9700009432 
I 
And/or 
ClinSync Clinical Research Pvt. Ltd. 
Clinical Pharmacology Department, 
#4-1- I ,Hayathnagar,Hyderabad, 
Telangana-50 1505, India. 
j Phon; no.: +91-40-2420300!/2/3 
) 
Fax no.: +9 I -40-24203000. 
X-Ray Facility 
I Srikara Hospitals 
#222&223, M}thri Nagar,Phase-11, 
Madinaguda, Miyapur, 
Hyderabad-500049, 
Ph: +91 40 -47470000, + 91 772 999 
0002. 
And/or 
ClinSync Clinical Research Pvt. Ltd. 
Clinical Pharmacology Department, 
~~a~e:~~~:~~;a:,::~l:, ~::::i,~aguda 
~~ 
Hyderabad-500050, 
Telangana, lndia. 
Phone no.: +91-40-24203001/2/3 
1 Fax no.: +91-40-24203000. 
I 
I 
25007 A-0 l 
Page 5 of7 


PROTOCOL Ai\IEi\Dt\IENT 
' SUNRISE HOSPITALS 
--r:,::;,:~::~:~t:·;:;;:~;--------· T----~----l 
I 
Si 
! 
! 
I 
H.#:4-9-321, Plot#4& 7, 
Hayathnagar, R.R. Dist, 
Hyderabad-50 1505. 
Phone no.: 9700009432 
\ #222&223, M)1hri Nagar, Phas~wll, 
Madinaguda, Miyapur, 
Hyderabad-500049, 
Ph: +91 40-47470000, 
+ 91 772 999 0002 
The plasma samples will be then 
The plasma samples will be stored in a 
16.4 Sampling 
I 
stored upright in a box containing 
dry ice or in a treezer at a 
temperature of -20 ± soc for 
interim storage (pre-dose and post-
dose samples up to 4.00 hours) and 
then will be transferred to -70 ± 
freezer of CCM department at -70 .l 
I JOOC. 
I Procedure 
I 
i l5°C at the clinical site. 
Note: The: above said changes are applicable: throughout the protocol and related documents. 
Prepared By (MW): 
(Sign & date) 
Reviewed By (QA): 
(Sign & date) 
Approved By (PVC!): ___ 
ct:=_-"--c:=:->1~'\':--"'Yc-e-~.,..-zoo_'_~ ____ _ 
(Sign & date) 
25007A-Ol 
Change in 
storage 
temperature 
due to revision / 
of the SOP j 
I 
Page 6 of 7 


. : C
11'l5)''1C 
. Iii 
11 
3.'' 
PROTOCOL AMENDMENT 
Protocol No.: C-CMP-SPI-001 
I, on behalf of CMP Development LLC, USA, have read, understood and approve this Pro!ocol 
Amendment No.OJ; Dated on 19 Dec 201g lor conducting Ule study at ClinSync Clinical 
Research Pvt. Ltd as per their Procedures. 
Authorized signatory 
Gerald Sakowski 
Chief Executive Officer 
CMP Development LLC 
PO Box 147 
8026 US Highway 264A 
Farmville, NC 27828 
Telephone: (800)227-6637 
25007A-OI 
Page 7 of7 


Clinical Study Report for Drug-Drug Interaction Study of Spironolactone and Digoxin 
(Fasting Condition) 
Confidential 
16.1.2 SAMPLE CASE REPORT FORM 
Protocol No.: C-CMP-SPJ-00 I 

SAP_001.pdf: 
Statistical Analysis Plan: February 2018  
An open label, balanced, randomized, single-dose, two-treatment, two-sequence, twoperiod, 
crossover oral drug-drug interaction study of spironolactone (perpetrator) and Digoxin 
(substrate drug) in healthy adult human subjects under fasting condition. 
PHARMACOKINETIC ASSESSMENTS: 
Concentration data of subjects versus time, which are received after analysis of samples, will 
be included in the final data analysis. Data from subjects with missing concentration values 
(missed blood samples, lost samples, samples unable to be quantified) may be used if 
pharmacokinetic parameters can be estimated using remaining data points, otherwise data from 
these subjects will be excluded from the final analysis.  
All concentration values below the limit of quantification (BLQ) will be set to zero for all 
pharmacokinetic and statistical calculations. Any missing samples will be reported as ‘Missing’ 
and will be denoted as “M” while running pharmacokinetic and statistical analysis.  
The following pharmacokinetic parameters will be computed using noncompartmental model 
of Phoenix WinNonlin Professional Software Version 6.4 (Pharsight Corporation, USA) or 
above. 
Pharmacokinetic Parameters for digoxin in plasma:  
Primary Pharmacokinetic parameters  
Cmax : Maximum measured plasma concentration.  
AUC0-96 : Area under the plasma concentration versus time curve from time 0 to the 96 hour 
time point concentration, calculated by linear trapezoidal method.  
Secondary Pharmacokinetic parameters  
Tmax : Time to achieve maximum plasma concentration. If the maximum value occurs at more 
than one time point, Tmax is defined as the first time point with this value.  
Pharmacokinetic Parameters for digoxin in urine:  
CLR: Renal clearance Ae0−240h/AUC0−240 h  
fe: Unchanged drug excreted in urine  
For all the above computations, actual time points of the sample collection will be used in case 
of sample collection deviations.  
In clinical phase or sample analysis process, if 3 or more consecutive post dose samples for 
any subject are found to be missing, samples of such subjects will be analyzed but 
pharmacokinetic data of those subjects will be excluded from the final statistical analysis. 
Pharmacokinetic data of those subjects will be tabulated and reported in the study report as a 
separate table. However, the data of such subjects will also be considered for statistical analysis 
if the 3 consecutive post dose samples are the last three samples of elimination phase.  
If the pre-dose concentration appears to be > 5% of the Cmax in any subject at any period, the 
data of such a subject will be excluded from the statistical analysis. 


STATISTICAL ANALYSIS 
Statistical analysis will be performed by using SAS statistical software version 9.3 or above.  
Descriptive statistics of all the pharmacokinetic parameters will be computed and reported for 
digoxin. 
The log-transformed pharmacokinetic parameters Cmax and AUC0-96 were analysed using 
Type III sum of squares, with the main effects of formulation, period, sequence and subjects 
nested within sequence as random effect.  
Statistical analysis was performed using SAS® package (SAS Institute Inc., USA, Version 
9.3).  
The presence or absence of DDI between the two treatments (A and B) was concluded based 
on the statistical results of 90% confidence interval for the ratio of the geometric least squares 
mean for log-transformed pharmacokinetic parameters Cmax and AUC0-96 for Digoxin. 
Absence of drug-drug interaction would be established if the 90% CI for the ratio of population 
geometric means of log-transformed data of Cmax and AUC0-96 between two treatments (A 
and B), were in the equivalence limits of 80.00 - 125.00% for Digoxin.  
Renal clearance (CLR)/ Percent Recovered and unchanged drug excreted in urine (fe)/Amount 
Recovered for Digoxin in the presence and absence of spironolactone was provided as 
supportive data.