Conditions: Healthy Participants
Keywords: Phase I Pharmacokinetics Spironolactone/Hydrochlorothiazide film coated tablets Bioequivalence
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 42
Healthy volunteers: yes

Brief summary:
The purpose of the study is to understand how the body processes Spironolactone and Hydrochlorothiazide after taking Spironolactone and Hydrochlorothiazide film coated tablets manufactured at two sites: Viatris and Neolpharma by mouth.

The study is seeking for:

* Both male and female participants.
* participants who must be 18 to 75 years of age.
* Body Mass Index of participants should be 16 to 32 kilogram per meter squared and body weight should be more than 50 kilograms (110 pounds).

About 40 participants will enter the study (20 in each group). Study consists of two periods. On Day 1 of each period, participants will receive a single amount of Spironolactone and Hydrochlorothiazide tablets. The total duration of study will be 71 days. Follow up may occur via telephone after 35 days after taking the final tablet of the study medicine.

Detailed description:

Arms:
arm 1: Spironolactone/Hydrochlorothiazide (25 mg/25 mg) film coated tablets manufactured at Viatris. arm 2: Spironolactone/Hydrochlorothiazide (25 mg/25 mg) film coated tablets manufactured at Neolpharma.

Interventions: intervention 1: Spironolactone/Hydrochlorothiazide (25 mg/25 mg) film coated tablets from Viatris intervention 2: Spironolactone/Hydrochlorothiazide (25 mg/25 mg) film coated tablets from Neolpharma.
Intervention descriptions: intervention 1: Manufactured at Viatris intervention 2: Manufactured at Neolpharma.

Protocol document:
Prot_000.pdf: 
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Final Protocol, 28 September 2023
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Title Page
A SINGLE-DOSE, OPEN-LABEL, RANDOMIZED, 2-WAY, CROSS-OVER PIVOTAL 
BIOEQUIVALENCE STUDY TO QUALIFY MANUFACTURING SITE TRANSFER 
FROM VIATRIS TO NEOLPHARMA, FOR
SPIRONOLACTONE/HYDROCHLOROTHIAZIDE FILM COATED TABLETS IN
HEALTHY ADULT PARTICIPANTS UNDER FASTED CONDITIONS
Study Intervention Number:
PF-06832640
Study Intervention Name:
Spironolactone/Hydrochlorothiazide
US IND Number:
NDA 012616
EudraCT Number:
Not applicable
ClinicalTrials.gov ID:
Not applicable
Pediatric Investigational Plan Number:
Not applicable
Protocol Number:
B9531002
Phase:
1
Sponsor Legal Address:
Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Brief Title: Pivotal Bioequivalence Study of Spironolactone/Hydrochlorothiazide Film 
Coated Tablets to Qualify Manufacturing Site Transfer From Viatris to Neolpharma.
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.


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Document History
Document
Version Date
Original protocol
28 September 2023


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities .............................................................................................13
2. INTRODUCTION ...............................................................................................................18
2.1. Study Rationale .......................................................................................................18
2.2. Background .............................................................................................................18
2.2.1. Clinical Overview.......................................................................................19
2.3. Benefit/Risk Assessment.........................................................................................20
2.3.1. Risk Assessment.........................................................................................21
2.3.2. Benefit Assessment.....................................................................................22
2.3.3. Overall Benefit/Risk Conclusion................................................................22
3. OBJECTIVES AND ENDPOINTS.....................................................................................22
4. STUDY DESIGN.................................................................................................................22
4.1. Overall Design.........................................................................................................22
4.2. Scientific Rationale for Study Design.....................................................................23
4.2.1. Choice of Contraception/Barrier Requirements .........................................24
4.3. Justification for Dose ..............................................................................................24
4.4. End of Study Definition ..........................................................................................24
5. STUDY POPULATION......................................................................................................24
5.1. Inclusion Criteria.....................................................................................................25
5.2. Exclusion Criteria....................................................................................................25
5.3. Lifestyle Considerations..........................................................................................27
5.3.1. Contraception..............................................................................................27
5.3.2. Meals and Dietary Restrictions...................................................................27
5.3.3. Caffeine, Alcohol, and Tobacco .................................................................28
5.3.4. Activity .......................................................................................................28
5.4. Screen Failures ........................................................................................................29
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................29
6.1. Study Intervention(s) Administered........................................................................29


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6.1.1. Administration............................................................................................30
6.2. Preparation, Handling, Storage, and Accountability...............................................30
6.2.1. Preparation and Dispensing........................................................................31
6.3. Assignment to Study Intervention...........................................................................32
6.4. Blinding...................................................................................................................32
6.5. Study Intervention Compliance...............................................................................32
6.6. Dose Modification...................................................................................................32
6.7. Continued Access to Study Intervention After the End of the Study......................32
6.8. Treatment of Overdose............................................................................................32
6.9. Prior and Concomitant Therapy..............................................................................33
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................33
7.1. Discontinuation of Study Intervention ....................................................................33
7.1.1. Potential Cases of Acute Kidney Injury .....................................................34
7.1.2. ECG Changes..............................................................................................35
7.1.3. Pregnancy ...................................................................................................35
7.1.4. COVID-19 ..................................................................................................36
7.2. Participant Discontinuation/Withdrawal From the Study.......................................36
7.2.1. Withdrawal of Consent...............................................................................36
7.3. Lost to Follow-Up ...................................................................................................37
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................37
8.1. Administrative Procedures ......................................................................................37
8.2. Efficacy Assessments..............................................................................................38
8.3. Safety Assessments .................................................................................................38
8.3.1. Physical Examinations................................................................................38
8.3.2. Vital Signs ..................................................................................................39
8.3.2.1. Blood Pressure and Pulse Rate..................................................39
8.3.3. Electrocardiograms.....................................................................................39
8.3.4. Clinical Safety Laboratory Assessments ....................................................40
8.3.4.1. Alternative Facilities for Clinical Safety Laboratory 
Assessment ........................................................................................40
8.3.5. Pregnancy Testing ......................................................................................40
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................41


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8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......41
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................42
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................42
8.4.2. Method of Detecting AEs and SAEs ..........................................................42
8.4.3. Follow-Up of AEs and SAEs......................................................................42
8.4.4. Regulatory Reporting Requirements for SAEs...........................................43
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................43
8.4.5.1. Exposure During Pregnancy......................................................43
8.4.5.2. Exposure During Breastfeeding ................................................45
8.4.5.3. Occupational Exposure .............................................................45
8.4.6. Cardiovascular and Death Events...............................................................46
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................46
8.4.8. Adverse Events of Special Interest.............................................................46
8.4.8.1. Lack of Efficacy........................................................................46
8.4.9. Medical Device Deficiencies......................................................................46
8.4.10. Medication Errors.....................................................................................46
8.5. Pharmacokinetics ....................................................................................................47
8.6. Genetics...................................................................................................................48
8.6.1. Specified Genetics ......................................................................................48
8.6.2. Retained Research Samples for Genetics ...................................................48
8.7. Biomarkers ..............................................................................................................48
8.8. Immunogenicity Assessments.................................................................................48
8.9. Health Economics ...................................................................................................48
9. STATISTICAL CONSIDERATIONS ................................................................................48
9.1. Statistical Hypothesis ..............................................................................................49
9.2. Analysis Sets ...........................................................................................................49
9.3. Statistical Analyses .................................................................................................49
9.3.1. General Considerations...............................................................................50
9.3.2. Primary Endpoint(s) Analysis.....................................................................50
9.3.3. Secondary Endpoint(s) Analysis.................................................................51
9.3.4. Safety Analyses ..........................................................................................51


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9.3.5. Other Analyses............................................................................................51
9.4. Interim Analyses .....................................................................................................51
9.5. Sample Size Determination.....................................................................................52
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................53
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............53
10.1.1. Regulatory and Ethical Considerations ....................................................53
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................53
10.1.2. Financial Disclosure .................................................................................54
10.1.3. Informed Consent Process ........................................................................54
10.1.4. Data Protection .........................................................................................55
10.1.5. Committees Structure ...............................................................................55
10.1.5.1. Data Monitoring Committee ...................................................55
10.1.6. Dissemination of Clinical Study Data ......................................................56
10.1.7. Data Quality Assurance ............................................................................57
10.1.8. Source Documents....................................................................................58
10.1.9. Use of Medical Records............................................................................58
10.1.10. Study and Site Start and Closure ............................................................59
10.1.11. Publication Policy...................................................................................60
10.1.12. Sponsor’s Medically Qualified Individual..............................................60
10.2. Appendix 2: Clinical Laboratory Tests .................................................................62
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................63
10.3.1. Definition of AE .......................................................................................63
10.3.2. Definition of an SAE ................................................................................64
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................65
10.3.4. Reporting of SAEs....................................................................................69
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................70
10.4.1. Male Participant Reproductive Inclusion Criteria....................................70
10.4.2. Female Participant Reproductive Inclusion Criteria.................................70
10.4.3. Woman of Childbearing Potential ............................................................71


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10.4.4. Contraception Methods.............................................................................72
10.5. Appendix 5: Genetics............................................................................................73
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......75
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................77
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................77
10.7.2. Age-Specific Kidney Function Calculation Recommendations...............77
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations ...........................................................................................77
10.7.3. Kidney Function Calculation Tools..........................................................78
10.7.4. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................78
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ...................................79
10.9. Appendix 9: Prohibited Concomitant Medications That May Result in DDI.......81
10.10. Appendix 10: Abbreviations ...............................................................................83
11. REFERENCES ..................................................................................................................86
LIST OF TABLES
Table 1.
Study Schedule of Assessment.................................................................13
Table 2.
Pharmacokinetic Sampling Times (Period 1 and Period 2)......................17
Table 3.
Treatment Sequence..................................................................................23
Table 4.
PK Parameters ..........................................................................................50
Table 5.
Protocol-Required Laboratory Assessments.............................................62


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1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title: A single-dose, open-label, randomized, 2-way, cross-over pivotal 
bioequivalence study to qualify manufacturing site transfer from Viatris to Neolpharma, for 
Spironolactone/Hydrochlorothiazide film coated tablets in healthy adult participants under 
fasted conditions.
Brief Title: Pivotal bioequivalence study of Spironolactone/Hydrochlorothiazide film coated 
tablets to qualify manufacturing site transfer from Viatris to Neolpharma.
Regulatory Agency Identification Number(s):
US IND Number:
NDA 012616
EudraCT Number:
Not applicable
ClinicalTrials.gov ID:
Not applicable
Pediatric Investigational Plan Number:
Not applicable
Protocol Number:
B9531002
Phase:
1
Rationale:
The purpose of this study is to assess the bioequivalence (BE) between 
Spironolactone/Hydrochlorothiazide film coated tablets manufactured at Viatris 
Pharmaceuticals LLC, Puerto Rico (hereafter referred to as Viatris) and 
Spironolactone/Hydrochlorothiazide film coated tablets manufactured at Neolpharma, Inc., 
Puerto Rico (hereafter referred to as Neolpharma).
Objectives and Endpoints:
Objectives
Endpoints
Primary: 
Primary:

To demonstrate bioequivalence between 
Spironolactone/Hydrochlorothiazide 25 mg/25 mg 
film coated tablets manufactured at the proposed 
site (Neolpharma) vs 
Spironolactone/Hydrochlorothiazide 25 mg/25 mg 
film coated tablets manufactured at current site 
(Viatris) under fasting conditions in healthy adult 
participants.

Maximum observed concentration (Cmax), area 
under the plasma concentration-time profile 
from time 0 extrapolated to infinite time 
(AUCinf) (or AUClast if AUCinf cannot be 
reliably estimated) of Spironolactone and 
Hydrochlorothiazide.


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Objectives
Endpoints
Secondary: 
Secondary:

To further characterize pharmacokinetic(s) (PK) of 
Spironolactone and Hydrochlorothiazide.

To evaluate the safety and tolerability of 
Spironolactone/Hydrochlorothiazide film coated 
tablets.

Terminal elimination half-life (t½) (if data 
permit) and time for Cmax (Tmax) of 
Spironolactone and Hydrochlorothiazide.

Adverse events (AEs), clinical laboratory tests, 
vital signs, and ECGs.
Overall Design:
This will be an open-label, randomized, single-dose, 2-treatment, 2-period, 2-sequence, 
crossover study in adult healthy male and/or female participants.
Number of Participants:
Approximately 40 participants will be enrolled in the study.
Note: “Enrolled” means a participant’s, or their legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and randomization/assignment to study intervention.
Study Population:
Key inclusion and exclusion criteria are listed below:
Inclusion Criteria
Participants must meet the following key inclusion criteria to be eligible for enrollment into 
the study:
1. Male and female participants must be 18 to 75 years of age, inclusive, at the time of 
signing the informed consent document (ICD).
2. Body mass index (BMI) of 16-32 kg/m2; and a total body weight >50 kg (110 lb).
Exclusion Criteria
Participants with any of the following characteristics/conditions will be excluded:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).


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
Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy).

History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, or HCVAb. Hepatitis B vaccination is allowed.
2. Baseline 12-lead electrocardiogram (ECG) that demonstrates clinically relevant 
abnormalities that may affect participant safety or interpretation of study results (eg,
baseline corrected QT (QTc) interval >450 msec.
Study Arms and Duration:
Approximately 40 participants will be enrolled in the study (20 in each treatment sequence). 
Participants will be assigned to 1 of the following 2 sequences according to a 
computer-generated randomization schedule. There will be a minimum 4-day washout period 
between successive doses (ie, administration of subsequent doses of study medication will 
not occur until at least 4 days after the previous dose of study medication).
Study Intervention(s)
Intervention Name
Spironolactone/Hydrochlorothiazide
Spironolactone/Hydrochlorothiazide
Use
Reference Product
Test Product
IMP or NIMP/AxMP
NIMP
IMP
Dose Formulation
Film coated tablets
Film coated tablets
Unit Dose Strength(s)
25 mg/25 mg
25 mg/25 mg
Route of Administration
Oral
Oral
Abbreviations: AxMP = auxiliary medicinal product; IMP = investigational medicinal product;
NIMP = noninvestigational medicinal product.
Study Arm(s)
Arm Title
Treatment A (Reference)
Treatment B (Test)
Arm Description
Participants will receive 
Spironolactone/Hydrochlorothiazide 
25 mg/25 mg film coated tablet 
manufactured at Viatris on Day 1 of 
each treatment period.
Participants will receive 
Spironolactone/Hydrochlorothiazide 
25 mg/25 mg film coated tablet 
manufactured at Neolpharma on Day 1 
of each treatment period.
Statistical Methods:
A sample size of 38 evaluable participants will provide ≥99.9% and 91.0% power that the 
90% confidence interval (CI) for the ratio of Test to Reference treatment for Cmax and AUCinf


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(or AUClast if AUCinf cannot be reliably estimated) of spironolactone, respectively, will lie 
within the acceptance region of (80%, 125%). Additionally, it will provide ≥99.6% and 
≥99.0% power that the 90% CIs for the ratios of Test to Reference treatment for AUCinf and 
Cmax of Hydrochlorothiazide (HCTZ) will lie within the acceptance region of (80%, 125%). 
Consequently, this study will have approximately 90% overall power to demonstrate BE of 
the Test treatment to the Reference treatment (ie, equivalence for both AUCinf and Cmax) of 
both spironalactone and HCTZ, where overall power for the study is based on the product of 
the individual powers of the parameters of interest.
Bioequivalence of the Test treatment to Reference treatment will be concluded if the 
90% CIs for the ratios of adjusted geometric means for both spironolactone and 
hydrochlorothiazide AUCinf and Cmax fall entirely within the acceptance region of (80%, 
125%).
Ethical Considerations:
Spironolactone/Hydrochlorothiazide film coated tablets are not expected to provide any 
clinical benefit to healthy participants. This study is designed primarily to generate 
pharmacokinetic and tolerability data of spironolactone and hydrochlorothiazide to support 
regulatory registration of Spironolactone/Hydrochlorothiazide film coated tablets at 
25 mg/25 mg strength manufactured at Neolpharma.


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1.2. Schema
Treatment Sequence
Sequence
Number of Participants
Period 1
Washout Period
Period 2
1
20
Treatment A
At least 4 days
Treatment B
2
20
Treatment B
Treatment A
Treatment A: Spironolactone/Hydrochlorothiazide 25 mg/25 mg film coated tablets manufactured at the 
current site (Viatris) under fasting conditions.
Treatment B: Spironolactone/Hydrochlorothiazide 25 mg/25 mg film coated tablets manufactured at the 
proposed site (Neolpharma) under fasting conditions.


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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 10.
Screening
Period 1
Period 2
F/U
Early 
Discontinuation
Notes
Days Relative to Day 1
Day -28 to Day -2 Day -1 Day 1 Day 2
Day 3
Day 1 Day 2 Day 3
28-35
Days

All screening should be done 
≤28 days before the first dose.

Day relative to start of study 
intervention (Day 1).

A washout period of at least 4 days 
(96 hours) will be required between 
the 2 doses.

Follow-up may occur via telephone 
contact and must occur 28 to 
35 days after administration of the 
final dose of study intervention.
Hours After Dose
0
24
48
0
24
48
Informed consent
X

Informed consent should be 
obtained prior to undergoing any 
study-specific procedures.

See Section 10.1.3 for additional 
information.
CRU confinement
X





X

Participants will enter CRU on 
Day -1 and stay in CRU until 
completion of Period 2 PK blood 
sampling.
Inclusion/exclusion 
criteria
X
X


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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 10.
Screening
Period 1
Period 2
F/U
Early 
Discontinuation
Notes
Days Relative to Day 1
Day -28 to Day -2 Day -1 Day 1 Day 2
Day 3
Day 1 Day 2 Day 3
28-35
Days

All screening should be done 
≤28 days before the first dose.

Day relative to start of study 
intervention (Day 1).

A washout period of at least 4 days 
(96 hours) will be required between 
the 2 doses.

Follow-up may occur via telephone 
contact and must occur 28 to 
35 days after administration of the 
final dose of study intervention.
Hours After Dose
0
24
48
0
24
48
Medical/medication 
history
X
X
Physical examinations
X
X
X
Safety laboratory
X
X
X

Safety laboratory includes 
hematology, chemistry, and 
urinalysis, which are listed in 
Appendix 2.

Laboratory safety tests will be 
obtained after fasting for at least 
8 hours.
Demography, age, weight 
and height
X
Illegal
drug/tobacco/alcohol use
X
X

For confirmation of no 
drug/tobacco/alcohol use.
Urine alcohol test or
alcohol breath test
X
X
Urine Pregnancy test 
(WOCBP only)
X
X
X

See Section 8.3.5 for additional 
information.


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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 10.
Screening
Period 1
Period 2
F/U
Early 
Discontinuation
Notes
Days Relative to Day 1
Day -28 to Day -2 Day -1 Day 1 Day 2
Day 3
Day 1 Day 2 Day 3
28-35
Days

All screening should be done 
≤28 days before the first dose.

Day relative to start of study 
intervention (Day 1).

A washout period of at least 4 days 
(96 hours) will be required between 
the 2 doses.

Follow-up may occur via telephone 
contact and must occur 28 to 
35 days after administration of the 
final dose of study intervention.
Hours After Dose
0
24
48
0
24
48
Contraception check
X
X
X
X

For confirmation of appropriate use 
only.

See Section 5.3.1 for additional 
information.
FSH (Post menopausal 
women only)
X
Urine drug testing
X
Single supine 12-Lead 
ECG
X
X

See Section 8.3.3 for additional 
information.
Blood pressure, pulse rate
X
X

See Section 8.3.2.1 for additional 
information.
HIV, HBsAg, HBcAb,
HCVAb 
X
Study intervention
administration
X
X

A washout period of at least 4 days 
(96 hours) will be required between 
the 2 doses.

The 1st dose will be administered on 
Study Day 1 (Period 1 Day 1) and 
the 2nd dose will be administered on 
Study Day 5 (Period 2 Day 1).
Pharmacokinetic blood 
sampling
X
X
X
X
X
X
X

Refer to PK sampling times table 
(Table 2).


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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 10.
Screening
Period 1
Period 2
F/U
Early 
Discontinuation
Notes
Days Relative to Day 1
Day -28 to Day -2 Day -1 Day 1 Day 2
Day 3
Day 1 Day 2 Day 3
28-35
Days

All screening should be done 
≤28 days before the first dose.

Day relative to start of study 
intervention (Day 1).

A washout period of at least 4 days 
(96 hours) will be required between 
the 2 doses.

Follow-up may occur via telephone 
contact and must occur 28 to 
35 days after administration of the 
final dose of study intervention.
Hours After Dose
0
24
48
0
24
48
Retained Research 
Sample for Genetics 
(Prep D1)
X

Prep D1 Retained Research 
Samples for Genetics: If not 
collected on the designated 
collection day, collect at the next 
available time point when 
biospecimens are being collected in 
conjunction with a participant visit.
CRU discharge
X
Concomitant medications
X
X
X
X
X
X
X
X
Serious and nonserious 
AE monitoring
X
X
X
X
X
X
X
X
X
X

See Section 8.4.3 for follow-up AE 
and SAE assessments.


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Table 2.
Pharmacokinetic Sampling Times (Period 1 and Period 2)
Visit Identifier
Period 1 and Period 2
Notes
Study Day
1
2
3
Hours Before/After Dose
0
0.25
0.5
1
1.5
2
2.5
3
4
6
8
10
12
24
36
48
Hour 0 = predose sample 
collection
Study intervention 
administration
X
PK blood sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Predose PK sample to be 
collected prior to dosing


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2. INTRODUCTION
Spironolactone/Hydrochlorothiazide film coated tablets are a combination of 2 diuretic 
agents spironolactone and hydrochlorothiazide indicated for treatment of essential 
hypertension, congestive heart failure, liver cirrhosis, nephrotic syndrome and other 
edematous conditions. Spironolactone and hydrochlorothiazide have different but 
complementary mechanisms and sites of action, thereby providing additive diuretic and 
antihypertensive effects.
2.1. Study Rationale
Pfizer Inc. is a marketing authorization holder for Spironolactone/Hydrochlorothiazide film 
coated tablets. It is currently marketed in the United States as 25 mg/25 mg 
(Spironolactone/Hydrochlorothiazide) film coated tablets.
Currently Spironolactone/Hydrochlorothiazide film coated tablets are manufactured at Viatris 
Pharmaceuticals LLC, Puerto Rico (hereafter referred to as Viatris). PGS intends to transfer 
drug product manufacturing operations for Spironolactone/Hydrochlorothiazide film coated 
tablets from the currently registered Viatris manufacturing site to the proposed Neolpharma, 
Inc., Puerto Rico (hereafter referred to as Neolpharma) manufacturing site. The f2 could not 
be calculated due to high %RSD values (high variability). Bootstrap f2 analysis was 
performed, and the similarity factor calculated was outside of acceptable range. The 
comparative dissolution profile data between existing site and proposed new site when tested 
in release media failed as the similarity factor (f2) calculated did not pass the criterion (f2 
value being <50) for both spironolactone and hydrochlorothiazide in release media tested. 
Therefore, this BE study is being conducted to qualify the manufacturing site transfer, and 
the associated process changes, by demonstrating BE between 
Spironolactone/Hydrochlorothiazide film coated tablets manufactured at the proposed site 
(Neolpharma) versus existing site (Viatris).
The primary objective of this study is to assess the BE between 
Spironolactone/Hydrochlorothiazide 25 mg/25 mg film coated tablets manufactured at 
Viatris and Spironolactone/Hydrochlorothiazide 25 mg/25 mg film coated tablets 
manufactured at Neolpharma.
2.2. Background
The current Spironolactone/Hydrochlorothiazide film coated tablets manufacturing needs to 
be transferred from Viatris to Neolpharma. The f2 could not be calculated due to high %RSD 
values (high variability). Bootstrap f2 analysis was performed, and the similarity factor 
calculated was outside of acceptable range. The comparative dissolution profile data between 
existing site and proposed new site when tested in release media failed as the similarity factor 
(f2) calculated did not pass the criterion (f2 value being <50) for both spironolactone and 
hydrochlorothiazide in release media tested. Hence, this BE study is being conducted to 
qualify the manufacturing site transfer from Viatris to Neolpharma.


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2.2.1. Clinical Overview
Spironolactone/Hydrochlorothiazide film coated tablets are a combination of 2 diuretic 
agents, spironolactone and hydrochlorothiazide, indicated for treatment of essential 
hypertension, congestive heart failure, liver cirrhosis, nephrotic syndrome and other 
edematous conditions. Spironolactone and HCTZ have different but complementary 
mechanisms and sites of action, thereby providing additive diuretic and antihypertensive 
effects. The spironolactone component of Spironolactone/Hydrochlorothiazide film coated 
tablets helps to minimize the potassium loss characteristically induced by the HCTZ 
component.
The diuretic effect of spironolactone is mediated through its action as a specific 
pharmacologic antagonist of aldosterone, primarily by competitive binding of receptors at the 
aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. 
HCTZ promotes the excretion of sodium and water primarily by inhibiting their reabsorption 
in the cortical diluting segment of the distal renal tubule.
Spironolactone/Hydrochlorothiazide is effective in significantly lowering the systolic and 
diastolic blood pressure in many patients with essential hypertension, even when aldosterone 
secretion is within normal limits.
Both spironolactone and HCTZ reduce exchangeable sodium, plasma volume, body weight, 
and blood pressure. The diuretic and antihypertensive effects of the individual components 
are potentiated when spironolactone and HCTZ are given concurrently.
Spironolactone/Hydrochlorothiazide is contraindicated in patients with acute renal 
insufficiency, significant renal compromise, anuria, Addison’s disease; significant 
hypercalcemia; hyperkalemia, or hypersensitivity to spironolactone, thiazide diuretics, or to 
other sulfonamide-derived drugs.
Spironolactone/Hydrochlorothiazide film coated tablets formulations are available in 
strengths of 25 mg/25 mg (Spironolactone/Hydrochlorothiazide).
Following oral administration, spironolactone rapidly gets absorbed with peak plasma 
concentrations reached within 1 hour post dosing. Following oral administration of a single 
100 mg dose of spironolactone, the mean AUCinf of spironolactone was approximately 
154 ng•hr/mL, mean Cmax was 48.3 ng/mL and elimination half-life of 2 to 3 hours (Xu et al, 
2008). Food increased the bioavailability of unmetabolized spironolactone by almost 100%. 
The clinical importance of this finding is not known (USPI, 09 January 2023).
Spironolactone is rapidly and extensively metabolized by both the kidneys and liver. 
Following deacetylation and S-methylation, spironolactone is converted to 
7-α-thiomethylspironolactone, a sulfur-containing active metabolite that is considered the 
major metabolite of spironolactone in serum. Sulfur-containing products are thought to be 
primarily responsible, together with spironolactone, for the therapeutic effects of the drug. 
Approximately 25% to 30% of spironolactone is also converted to canrenone by 
dethioacetylation (non-sulfur-containing active metabolite) (CDS, 14 April 2022). 


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Spironolactone and its metabolites are more than 90% bound to plasma proteins. The 
metabolites are excreted primarily in the urine and secondarily in bile.
In a PK study in 5 healthy male volunteers receiving spironolactone 500 mg, 47% to 57% of 
the dose was excreted in the urine within 6 days and the remaining amount could be detected 
in the feces (total recovery 90%). In another study in 5 healthy men, after a single 200 mg 
(with radioactive tracer) dose of spironolactone administration, over 5 days, 31.6% ± 5.87% 
of the radioactivity was excreted in the urine mainly as metabolites and 22.7% ± 14.1% in the 
feces (CDS, 14 April 2022).
HCTZ is rapidly absorbed following oral administration. HCTZ peak plasma concentrations 
reached within 1 to 2 hours. Concurrent administration of HCTZ with food has resulted in 
significant decreases in plasma drug levels as compared to the administration of HCTZ in a 
fasted state (USPI, 09 January 2023). Following oral administration of a single 50 mg dose of 
hydrochlorthiazide, the mean AUCinf of hydrochlorthiazide was approximately 
1730 ng•hr/mL, mean Cmax was 281 ng/mL and elimination half-life of approximately 
10 hours (Fierro Humberto, 2016).
HCTZ is approximately 40% protein bound and accumulates in erythrocytes by an unknown 
mechanism. The ratio between red blood corpuscles and plasma is 3.5:1. The volume of 
distribution of HCTZ is approximately 3 L/kg to 4 L/kg (CDS, 14 April 2022).
HCTZ undergoes only slight metabolic alteration and is excreted unchanged in urine. 
Following oral administration of 4 different doses (12.5 mg, 25 mg, 50 mg and 75 mg) of 
HCTZ to 8 healthy volunteers, renal clearance ranged between 319 mL/min and 345 mL/min. 
HCTZ is excreted unchanged in the urine and appears in the urine within 1 hour of dosing. 
Approximately 50% to 70% was recovered in the urine within 24 hours after the oral 
administration of 25 mg to 65 mg of HCTZ.
Spironolactone has been shown to be tumorigenic in chronic toxicity studies in rats, thus 
unnecessary use of this drug should be avoided.
2.3. Benefit/Risk Assessment
Spironolactone/Hydrochlorothiazide film coated tablets are not expected to provide any 
clinical benefit to healthy participants. This study is designed primarily to generate safety, 
tolerability, and PK data for further clinical development.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of Spironolactone/Hydrochlorothiazide film coated tablets may be found in the 
package insert, which is the SRSD for this study. Refer to the Study Intervention(s) table in 
Section 6.1 for a complete description of SRSDs.


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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s): Spironolactone/Hydrochlorothiazide Film Coated Tablets
Tumorigenic
The potential risk is based on pre-clinical toxicology 
findings for Spironolactone and HCTZ.
Eligibility criteria have been selected to ensure only 
appropriate participants are included in the study and 
study procedures are in place to evaluate this risk 
ie, physical examination. AEs will be closely 
monitored.


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2.3.2. Benefit Assessment
Spironolactone/Hydrochlorothiazide film coated tablets are not expected to provide any 
clinical benefit to healthy participants.
2.3.3. Overall Benefit/Risk Conclusion
Spironolactone/Hydrochlorothiazide film coated tablets are not expected to provide any 
clinical benefit to healthy participants. This study is designed primarily to generate PK, 
safety and tolerability data of spironolactone and hydrochlorothiazide to support regulatory 
registration of Spironolactone/Hydrochlorothiazide 25 mg/25 mg strength film coated tablets 
manufactured at Neolpharma.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary:
Primary:

To demonstrate bioequivalence between 
Spironolactone/Hydrochlorothiazide 
25 mg/25 mg film coated tablets manufactured 
at the proposed site (Neolpharma) vs 
Spironolactone/Hydrochlorothiazide 
25 mg/25 mg film coated tablets manufactured 
at current site (Viatris) under fasting conditions 
in healthy adult participants.

Cmax, AUCinf (or AUClast if AUCinf cannot be 
reliably estimated) of Spironolactone and 
Hydrochlorothiazide.
Secondary:
Secondary:

To further characterize PK of Spironolactone 
and Hydrochlorothiazide.

To evaluate the safety and tolerability of 
Spironolactone/Hydrochlorothiazide film 
coated tablets.

t½ (if data permit) and Tmax of Spironolactone 
and Hydrochlorothiazide.

AEs, clinical laboratory tests, vital signs, and 
ECGs.
4. STUDY DESIGN
4.1. Overall Design
This will be an open-label, randomized, single-dose, 2-treatment, 2-period, 2-sequence, 
crossover study in adult healthy male and/or female participants. Approximately 
40 participants will be enrolled in the study (20 in each treatment sequence). Dropouts for 
non-safety reasons or non-evaluable participants may be replaced at the discretion of the 
sponsor and investigator. Screening evaluation will occur within 28 days prior to the first 
dose of study medication. Participants will be assigned to 1 of the following 2 sequences 
according to a computer-generated randomization schedule.


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Table 3.
Treatment Sequence
Sequence
Number of Participants
Period 1
Washout Period
Period 2
1
20
Treatment A
At least 4 days
Treatment B
2
20
Treatment B
Treatment A
Treatment A: Spironolactone/Hydrochlorothiazide 25 mg/25 mg film coated tablets manufactured at the 
current site (Viatris) under fasting conditions.
Treatment B: Spironolactone/Hydrochlorothiazide 25 mg/25 mg film coated tablets manufactured at the 
proposed site (Neolpharma) under fasting conditions.
There will be a minimum 4-day washout period between successive doses (ie, administration 
of subsequent doses of study medication will not occur until at least 4 days after the previous 
dose of study medication).
Screening evaluation will occur within 28 days prior to the first dose of study medication. 
Day -1 is defined as the day prior to the first day of dosing (Day 1) in each period.
Participants will be admitted to the CRU on Day -1 and will remain confined in the CRU 
from Period 1 through Period 2 until the collection of the 48-hour PK sample making it a 
total of 8 days and 7 nights including Day -1. The washout period between the 2 successive 
dosing’s will be at least 4 days (96 hours).
On Day 1 of each period, participants will receive a single dose of investigational product as 
per randomization schedule. Study treatments will be administered with 240 mL of ambient 
temperature water under fasted conditions (overnight fast and no food until 4 hours after 
dosing). Water will be allowed without restriction until 1 hour prior to dosing and may be 
consumed without restriction beginning 1 hour after dosing.
Blood samples for the analysis of spironolactone and HCTZ in plasma will be obtained 
predose (immediately prior to dosing) and postdose as outlined in the Schedule of Activities.
Tolerability and safety will be assessed for all treatments by monitoring AEs.
4.2. Scientific Rationale for Study Design
Currently Spironolactone/Hydrochlorothiazide film coated tablets are manufactured at 
Viatris. PGS intends to transfer drug product manufacturing operations for 
Spironolactone/Hydrochlorothiazide film coated tablets from the currently registered Viatris 
manufacturing site to the proposed Neolpharma manufacturing site. The f2 could not be 
calculated due to high %RSD values (high variability). Bootstrap f2 analysis was performed, 
and the similarity factor calculated was outside of acceptable range. The comparative 
dissolution profile data between existing site and proposed new site when tested in release 
media failed as the similarity factor (f2) calculated did not pass the criterion (f2 value being 
<50) for both Spironolactone and hydrochlorothiazide in release media tested. Therefore, this 
BE study is being conducted to qualify the manufacturing site transfer, and the associated 
process changes, by demonstrating BE between Spironolactone/Hydrochlorothiazide film 
coated tablets manufactured at the proposed site (Neolpharma) versus existing site (Viatris).


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4.2.1. Choice of Contraception/Barrier Requirements 
Spironolactone/Hydrochlorothiazide is known to cause risk for severe manifestations of 
developmental toxicity in humans or suspected on the basis of the nonclinical 
studies. Therefore, the use of a highly effective method of contraception is required (see 
Appendix 4).
Nonclinical studies suggest risk for severe manifestations of developmental toxicity at 
relevant clinical exposures for Spironolactone/Hydrochlorothiazide. Therefore, the use of a 
highly effective method of contraception is required (see Appendix 4).
Studies to evaluate the developmental toxicity of Spironolactone/Hydrochlorothiazide have 
not been conducted. Therefore, the use of a highly effective method of contraception is 
required (see Appendix 4).
4.3. Justification for Dose
Spironolactone/Hydrochlorothiazide film coated tablets have a dose strength equivalent to 
25 mg/25 mg respectively. Since this is the only dose that will be transferred from Viatris to 
Neolpharma for spironolactone and hydrochlorothiazide, a BE study will be conducted for 
the 25 mg/25 mg strength.
4.4. End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study 
or last scheduled procedure shown in the SoA for the last participant in the trial globally.
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last visit or the last scheduled procedure shown in the SoA.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.


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5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male and female participants must be 18 to 75 years of age, inclusive, at the time of 
signing the ICD.
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Other Inclusion Criteria:
2. BMI of 16-32 kg/m2; and a total body weight >50 kg (110 lb).
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
4. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).

Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy).

History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, or HCVAb. Hepatitis B vaccination is allowed.
2. Any medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of
study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
Prior/Concomitant Therapy:
3. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 


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intervention. (Refer to Section 6.9 Prior and Concomitant Therapy for additional 
details).
4. Current use of any prohibited concomitant medication(s) or participant unwilling or 
unable to use a required concomitant medication(s). Refer to Section 6.9 Prior and 
Concomitant Therapy.
Prior/Concurrent Clinical Study Experience:
5. Previous administration with an investigational product (drug or vaccine) within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer). Participation in 
studies of other investigational products (drug or vaccine) at any time during their 
participation in this study.
Diagnostic Assessments:
6. A positive urine drug test. A single repeat for positive drug screen may be allowed.
7. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If systolic BP is ≥ 140 or 150 mm Hg (based on age) or
diastolic ≥90 mm Hg, the BP should be repeated 2 more times and the average of the 
3 BP values should be used to determine the participant’s eligibility. 
8. Hepatic dysfunction defined as:

Total bilirubin ≥1.5 × ULN (For Gilbert’s syndrome, direct bilirubin >ULN is 
exclusionary)

AST ≥1.5 × ULN

ALT ≥1.5 × ULN
9. Baseline standard 12-lead ECG that demonstrates clinically relevant abnormalities 
that may affect participant safety or interpretation of study results (eg, QTcF >450 
ms). If QTcF exceeds 450 ms, the ECG should be repeated twice and the average of 
the 3 QTcF values used to determine the participant’s eligibility. Computer-
interpreted ECGs should be overread by a physician experienced in reading ECGs 
before excluding a participant.
Other Exclusion Criteria:
10. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine).


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11. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
12. History of sensitivity to heparin or heparin induced thrombocytopenia. 
13. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
14. History of hypersensitivity to spironolactone or HCTZ or any of the components in 
the formulation of the study products, or allergic to thiazide diuretics or to other 
sulfonamide-derived drugs.
15. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Contraception
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Appendix 4,
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use. The investigator or designee will advise the participant to seek advice about the 
donation and cryopreservation of germ cells prior to the start of study intervention, if 
applicable.
At time points indicated in SoA, the investigator or designee will inform the participant of 
the need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart. Participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception, 
considering that their risk for pregnancy may have changed since the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.3.2. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the predose 
PK sample.


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
Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after dosing. Noncaffeinated drinks 
(except grapefruit or grapefruit-related citrus fruit juices—see below) may be 
consumed with meals and the evening snack.

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample. 

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.3. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period. 

Participants will abstain from alcohol for 24 hours prior or as specified above for red 
wine to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample of each study period. Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator.

Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.

Smoking may be allowed according to CRU practices. Smoking will not be permitted 
during frequent sampling procedures, and will not be permitted within 2 hours prior 
to any vital sign or ECG assessments. Smoking will also not be permitted 2 hours 
before and 2 hours following any dose of study intervention.
5.3.4. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted;

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing.


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5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Screen failure data are collected and remain as 
source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and medical devices, and other 
interventions (eg, surgical and behavioral) intended to be administered to the study 
participants during the study conduct.
For the purposes of this protocol, study intervention refers to
Spironolactone/Hydrochlorothiazide film coated tablets.
6.1. Study Intervention(s) Administered
Study Intervention(s)
Intervention Name
Spironolactone/Hydrochlorothiazide
Spironolactone/Hydrochlorothiazide
Type
Drug
Drug
Use
Reference Product
Test Product
IMP or NIMP/AxMP
NIMP
IMP
Dose Formulation
Film Coated Tablets
Film Coated Tablets
Unit Dose Strength(s)
25 mg/25 mg
25 mg/25 mg
Dosage Level(s)
Single dose 
Single dose
Route of 
Administration
Oral
Oral
Sourcing
Provided centrally by the sponsor
Provided centrally by the sponsor
Packaging and 
Labeling
Study intervention will be provided 
in unit dose containers as unblinded. 
Each container will be labeled as 
required per country requirement.
Study intervention will be provided in 
unit dose containers as unblinded. Each 
container will be labeled as required per 
country requirement.
SRSD
Package Insert
Package Insert
Current Name(s)
Spironolactone/Hydrochlorothiazide
Spironolactone/Hydrochlorothiazide


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Study Arm(s)
Arm Title
Treatment A (Reference)
Treatment B (Test)
Arm Description
Participants will receive 
Spironolactone/Hydrochlorothiazide 
25 mg/25 mg film coated tablet 
manufactured at Viatris on Day 1 of 
each treatment period.
Participants will receive 
Spironolactone/Hydrochlorothiazide 
25 mg/25 mg film coated tablet 
manufactured at Neolpharma on 
Day 1 of each treatment period.
Pivotal BA/BE study film coated tablets will be supplied to the CRU in multidose labeled 
containers (in sufficient number to allow unopened containers to be kept as retains).
6.1.1. Administration
Following an overnight fast of at least 10 hours, participants will receive study intervention
at approximately 0800 hours (plus or minus 2 hours). Investigator site personnel will 
administer study intervention during each period with ambient temperature water to a total 
volume of approximately 240 mL.
Participants will swallow the study intervention whole, and will not manipulate or chew the 
study intervention prior to swallowing.
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for BP, pulse rate, and ECG 
measurements), eating, and drinking beverages other than water during the first 4 hours after 
dosing.
Administration of study intervention(s) at the site will be performed by an appropriately 
qualified and trained member of the study staff as allowed by local, state, and institutional 
guidance.
Following administration of study intervention(s) at the site, participants will be observed for 
4 hours by an appropriately qualified and trained member of the study staff. Appropriate 
medication and other supportive measures for management of a medical emergency will be 
available in accordance with local guidelines and institutional guidelines.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention.
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 


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storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business.
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to the labeled storage conditions, 
as soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to
report for each excursion will be provided to the site in the IPM.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IPM. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
9. All pivotal BA/BE retains should be stored by the investigator site or with a 
third-party vendor. Sample retention is the responsibility of the entity performing the 
BA/BE study.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IPM.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 


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participant, in accordance with this protocol. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities.
Tablets will be prepared at the CRU in the individual dosing containers by 2 operators, 1 of 
whom is an appropriately qualified and experienced member of the study staff (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist). 
The tablets will be provided in unit dose containers and labeled in accordance with Pfizer 
regulations and the clinical site’s labeling requirements.
6.3. Assignment to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
6.4. Blinding
This is an open-label study.
As this is an open-label study, the sponsor may conduct reviews of the data during the course 
of the study for the purpose of safety assessment, facilitating dose-escalation decisions, 
facilitating PK/PD modeling, and/or supporting clinical development.
6.5. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.6. Dose Modification
Dose modification is not allowed in this single dose study.
6.7. Continued Access to Study Intervention After the End of the Study
No study intervention will be provided to participants at the end of their study participation.
6.8. Treatment of Overdose
For this study, any dose of Spironolactone/Hydrochlorothiazide greater than 25 mg/25 mg 
within a 24-hour time period will be considered an overdose.


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There is no specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the study medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and follow up until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis within 3 days from the date of the last dose of 
study intervention if requested by the study medical monitor (determined on a 
case-by-case basis).
6.9. Prior and Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. Acetaminophen/paracetamol may be used at doses of 
≤1 g/day.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Since this is a single-dose study, this section is not applicable.


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7.1.1. Potential Cases of Acute Kidney Injury
Participants exposed to IMP demonstrating transient or sustained increase in Screat (with 
decrease in Screat-based eGFR) require expedited evaluation to differentiate AKI from DICI.
DICI is defined as transporter-mediated effect related to altered renal tubular creatinine 
handling without histological injury.
AKI may be due to one or more types of injury, including DIKI. Differentiation of DIKI 
from other causes of AKI and from DICI may require clinical, radiographic, histopathologic, 
and laboratory assessments, as well as nephrology consultation.
Follow-up Assessments
The participant should return to the site for evaluation as soon as possible, preferably within 
48 hours of awareness of the abnormal results.
Evaluation should include physical examination, laboratory tests, detailed medical and 
surgical history, review of all medications (including recreational drugs and supplements 
[herbal]), family history, sexual history, travel history, blood transfusion, and potential 
occupational exposure to chemicals.
Laboratory assessments should include simultaneous serum cystatin C (Scys) and serum 
creatinine (Screat) tests. Estimates of eGFR and Screat-based eGFR and combined Screat-
Scys-based eGFR should also be derived using the appropriate equation described in 
Appendix 7.
Assessments of urine albumin-to-creatinine ratio or urine volume may also be performed as 
appropriate.
Differentiating Acute Kidney Injury from DICI
A confirmed Screat increase is defined as:
(i) ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours OR
(ii) confirmed Screat increase ≥1.5 times baseline (known or suspected to have occurred 
within the prior 7 days).
Based on the assessments performed, suspected AKI (including DIKI) may be differentiated 
from DICI as follows.


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Adult participants
AKI (including DIKI)
Any one of the below
DICI
Scys & Screat
Simultaneous, confirmed serum cystatin 
C (Scys) increase and confirmed Screat 
increase
Confirmed Screat increase without 
confirmed increase in reflex Scys
AND
Confirmed Screat-based eGFR 
decrease without confirmed combined 
Screat-Scys-based eGFR decrease.
eGFR
Decrease in Screat-based eGFR and 
combined Screat-Scys-based eGFR (when 
available)
Albuminuria or 
proteinuria
Confirmed albuminuria increase (see 
Appendix 7 for Grades A1 to A3 
quantitation)
Urine volume
Urine volume <0.5 mL/kg/h for 6 
consecutive hours
Regardless of the presence or absence of increase in Screat, DIKI and other causes of AKI 
may be suspected if either there is (i) new-onset or worsening albuminuria or proteinuria are 
detected.
All confirmed cases of clinically relevant decrease in kidney function should be considered 
potential cases of DIKI if no other reason for the kidney function abnormalities has been 
found.
7.1.2. ECG Changes
A participant who meets the bulleted criteria based on the average of triplicate ECG readings 
will be withdrawn from the study intervention.

QTcF >500 ms.

Change from baseline: QTcF >60 ms and QTcF >450 ms.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
7.1.3. Pregnancy
In the case of a positive confirmed pregnancy, the participant will be withdrawn from the 
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7.1.4. COVID-19
If a participant has COVID-19 during the study, this should be reported as an AE or SAE (as 
appropriate) and appropriate medical intervention provided. Study treatment should continue 
unless the investigator/treating physician is concerned about the safety of the participant, in 
which case temporary or permanent discontinuation may be required.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following: safety, behavioral, compliance, or 
administrative reasons.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.
The participant will be permanently discontinued from the study intervention and the study at 
that time.
If a participant withdraws from the study, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1 for 
disclosure of future information, no further evaluations will be performed and no additional 
data will be collected. The sponsor may retain and continue to use any data collected before 
such withdrawal of consent.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with them or persons previously authorized by the participant to provide this information. 
Participants should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of study intervention or also from study procedures and/or posttreatment study 
follow-up, and entered on the appropriate CRF page. In the event that vital status (whether 


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the participant is alive or dead) is being measured, publicly available information should be 
used to determine vital status only as appropriately directed in accordance with local law.
7.3. Lost to Follow-Up
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for/attend a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study.
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 


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investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
290 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 56 consecutive 
days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.2. Efficacy Assessments
Efficacy parameters are not evaluated in this study.
8.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
8.3.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight.
Physical examination findings collected during the study will be considered source record 
and will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 


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definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
8.3.2. Vital Signs
8.3.2.1. Blood Pressure and Pulse Rate
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
8.3.3. Electrocardiograms
Standard 12-lead ECGs will be collected at times specified in the SoA section of this
protocol using an ECG system that automatically calculates the HR and measures PR, QT, 
QTcF, and QRS intervals. All scheduled ECGs should be performed after the participant has 
rested quietly for at least 5 minutes in a supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) a 
postdose QTcF interval is increased by ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG. If either of these conditions occurs, 
then 2 additional ECGs will be collected approximately 2 to 4 minutes apart to confirm the 
original measurement. If the QTcF values from these repeated ECGs remain above the 
threshold value, then a single ECG must be repeated at least hourly until QTc values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement.
If a) a postdose QTcF interval remains ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner, at 
the discretion of the investigator); or c) QTcF value get progressively longer, the participant
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF
values do not return to less than the criteria listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator).


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In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 8.
8.3.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition.
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 28 calendar days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or study medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI.
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
8.3.4.1. Alternative Facilities for Clinical Safety Laboratory Assessment
Not applicable.
8.3.5. Pregnancy Testing
A urine or serum pregnancy test is required at screening. Following screening, pregnancy 
tests may be urine or serum tests, and must have a sensitivity of at least 25 mIU/mL. 
Pregnancy tests will be performed in WOCBP at the times listed in the SoA. Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced 
and a second negative pregnancy test result will be required at the baseline visit prior to 


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starting the Spironolactone/Hydrochlorothiazide film coated tablet. Pregnancy tests will also 
be done whenever 1 menstrual cycle is missed during the active treatment period (or when 
potential pregnancy is otherwise suspected) and at the end of the study. Pregnancy tests may 
also be repeated if requested by IRBs/ECs or if required by local regulations. If a urine test 
cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required. In such cases, the participant must be excluded if the serum pregnancy result is 
positive.
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study (see Section 7.1).
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention), through and including a minimum of 28 calendar days, except as indicated 
below, after the last administration of the study intervention.
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
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If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study because of an AE 
or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the CT 
SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has concluded study participation, and they
consider the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form.
8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available.
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.4.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.4.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 


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obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is provided in Appendix 3.
8.4.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if:

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.


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
A male participant who is receiving or has discontinued study intervention
inseminates a female partner.

A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP:

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or skin 
contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then inseminates his female 
partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy).

If EDP occurs in a participant/participant’s partner, the investigator must report this 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form regardless of whether an SAE has occurred. Details of the pregnancy will be 
collected after the start of study intervention and until 4 days that is at least 5 terminal 
half-lives after the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form. Since the exposure 
information does not pertain to the participant enrolled in the study, the information is 
not recorded on a CRF; however, a copy of the completed report is maintained in the 
investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial report. In the case of a live birth, the structural integrity of the neonate 
can be assessed at the time of birth. In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 


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for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study intervention by 
ingestion, inhalation, or skin contact. 
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the CT SAE Report Form. When EDB occurs in the setting of environmental exposure, 
the exposure information does not pertain to the participant enrolled in the study, so the 
information is not recorded on a CRF. However, a copy of the completed report is 
maintained in the investigator site file.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form regardless of 


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whether there is an associated SAE. Since the information about the occupational exposure 
does not pertain to a participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed report is maintained in the investigator site file.
8.4.6. Cardiovascular and Death Events
Not applicable.
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.4.8. Adverse Events of Special Interest
AESIs are examined as part of routine safety data review procedures throughout the clinical 
trial and as part of signal detection processes. Should an aggregate analysis indicate that 
these prespecified events occur more frequently than expected, eg, based on epidemiological 
data, literature, or other data, then this will be submitted and reported in accordance with 
Pfizer’s safety reporting requirements. Aggregate analyses of safety data will be performed 
on a regular basis per internal SOP. 
All AESIs must be reported as an AE or SAE following the procedures described in 
Section 8.4.1 through 8.4.4. An AESI is to be recorded as an AE or SAE on the CRF. In 
addition, an AESI that is also an SAE must be reported using the CT SAE Report Form.
8.4.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.4.9. Medical Device Deficiencies
Not applicable.
8.4.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE


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Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, such medication errors occurring to a study participant are recorded on the 
medication error page of the CRF, which is a specific version of the AE page and, if 
applicable, any associated serious and nonserious AE(s), are recorded on the AE page of the 
CRF.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Pharmacokinetics
Blood samples will be collected for measurement of plasma concentrations of HCTZ and 
Spironolactone as specified in the SoA. Instructions for the collection and handling of 
biological samples will be provided in the laboratory manual or by the sponsor. The actual 
date and time (24-hour clock time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of
samples up to and including 10 hours after dose administration that are obtained within 10% 
of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will not 
be captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows.
Samples will be used to evaluate the PK of spironolactone and HCTZ. Samples collected for 
analyses of spironolactone and HCTZ plasma concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study, for metabolite 
identification and/or evaluation of the bioanalytical method, or for other internal exploratory 
purposes. The exploratory results may not be reported in the CSR.
Genetic analyses will not be performed on these plasma samples. Participant confidentiality 
will be maintained.
Samples collected for measurement of plasma concentrations of spironolactone and HCTZ 
will be analyzed using a validated analytical method in compliance with applicable SOPs.


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The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
8.6.2. Retained Research Samples for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow.
Retained Research Samples may be used for research related to the study intervention(s). 
Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
retained samples.
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the lab manual.
8.7. Biomarkers
Biomarkers are not evaluated in this study.
8.8. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.


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9.1. Statistical Hypothesis
The alternative hypothesis of BE (H1: L <=T - R <=U), and the null hypothesis of 
inequivalence (Ho: T - R <L or T - R >U) can be expressed as the following 2 separate 
1-sided hypotheses:
HoA: T - R <L
H1A: L <=T - R
HoB: T - R >U
H1B: T - R <=U
Where T and R represent the average BA on a log scale for the Test and Reference 
products respectively and [L, U] defines the BE range.
BE of the Test treatment to Reference treatment will be concluded if the 90% CIs for the 
ratios of adjusted geometric means for both spironolactone and hydrochlorothiazide AUCinf
and Cmax fall entirely within the acceptance region of (80%, 125%).
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
Enrolled 
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
randomization. 
Full analysis set 
Example: All participants randomly assigned to study 
intervention and who take at least 1 dose of study intervention.
Safety analysis set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will 
be analyzed according to the product they actually received.
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
PK parameters will be derived from the concentration-time profiles as shown in Table 4. 
Actual PK sampling times will be used in the derivation of PK parameters.


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Table 4.
PK Parameters
Parameter
Definition
Method of Determination
AUClast
Area under the plasma concentration-time 
profile from time 0 to the time of the last 
quantifiable concentration (Clast)
Linear-log trapezoidal method
AUCinfa
Area under the plasma concentration-time 
profile from time 0 extrapolated to 
infinite time
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable time point 
estimated from the log-linear regression 
analysis.
Cmax
Maximum plasma concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
t½a
Terminal elimination half-life
Ln(2)/kel,
where kel is the terminal phase rate constant 
calculated by a linear regression of the log 
linear concentration-time curve. Only those 
data points judged to describe the terminal 
log-linear decline will be used in the 
regression.
a.
If data permits.
Actual PK sampling times will be used in the derivation of PK parameters. In the case that 
actual PK sampling times are not available, nominal PK sampling time will be used in the 
derivation of PK parameters.
9.3.1. General Considerations
Not applicable.
9.3.2. Primary Endpoint(s) Analysis
Pharmacokinetic and statistical analysis will be performed for spironolactone and 
hydrochlorothiazide.
Natural log transformed PK parameters (Cmax, AUCinf (or AUClast if AUCinf cannot be 
reliably estimated)) will be analyzed using a mixed effect model with sequence, period and 
treatment as fixed effects and participant within sequence as a random effect. Estimates of 
the adjusted mean differences (Test/ Reference) and the corresponding 90% CIs will be 
obtained from the model. The adjusted mean differences and the 90% CIs for the differences 
will be exponentiated to provide estimates of the ratio of adjusted geometric means (Test/ 
Reference) and the 90% CIs for the ratios.
For bioequivalence assement of Spironolactone/Hydrochlorothiazide 25/25 mg film coated 
tablets between proposed site (Neolpharma) and current site (Viatris), bioequivalence of the 
Test treatment (Treatment B) relative to Reference treatment (Treatment A) will be 
concluded if the 90% confidence intervals for the ratio of adjusted geometric means of Test 
treatment (Treatment B) relative to Reference treatment (Treatment A) for Cmax, AUCinf (or 
AUClast if AUCinf cannot be reliably estimated) fall wholly within (80%, 125%).


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9.3.3. Secondary Endpoint(s) Analysis
The secondary PK parameters like Tmax and t½ would be derived from the concentration-time 
profiles. AUCinf, area under the plasma concentration-time profile from time 0 extrapolated 
to infinite time is calculated from AUClast + (Clast*/kel), where Clast* is the predicted plasma 
concentration at the last quantifiable time point estimated from the log-linear regression 
analysis. Cmax is the maximum plasma concentration observed directly from the data. t½ is the 
terminal elimination half-life calculated from Ln(2)/kel, where kel is the terminal phase rate 
constant calculated by a linear regression of the log linear concentration-time curve. Only 
those data points judged to describe the terminal log-linear decline will be used in the 
regression.
The PK parameters AUClast, AUCinf, Cmax, Tmax, and t½ will be summarized descriptively by 
analyte and treatment. For AUCinf, AUClast, and Cmax parameters, individual data and 
geometric mean will be plotted with box plots by analyte and treatment for each parameter. 
Plasma concentration data will be listed and summarized descriptively by analyte, PK 
sampling time and treatment. Individual participant and summary profiles (mean and median) 
of the plasma concentration-time data will be plotted against analyte by treatment. Mean and 
median profiles will be presented on both linear-linear and log-linear scales. For summary 
statistics and summary (mean and median) plots by sampling time, the nominal PK sampling 
time will be used. For individual participant plots by time, the actual PK sampling time will 
be used.
9.3.4. Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants. Any clinical 
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 
described. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study, will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported.
9.3.5. Other Analyses
Not applicable.
9.4. Interim Analyses
No interim analysis will be conducted for this study.


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9.5. Sample Size Determination
A sample size of 38 evaluable participants will provide ≥99.9% and 91.0% power that the 
90% CI for the ratio of Test to Reference treatment for Cmax and AUCinf (or AUClast if AUCinf
cannot be reliably estimated) of spironolactone, respectively, will lie within the acceptance 
region of (80%, 125%). Additionally, it will provide ≥99.6% and ≥99.0% power that the 90% 
CIs for the ratios of Test to Reference treatment for AUCinf and Cmax of HCTZ will lie within 
the acceptance region of (80%, 125%). Consequently, this study will have approximately 
90% overall power to demonstrate BE of the Test treatment to the Reference treatment (ie, 
equivalence for both AUC and Cmax) of both spironolactone and HCTZ, where overall power 
for the study is based on the product of the individual powers of the parameters of interest.
These estimates are based on the assumption that the true ratio between Test and Reference 
treatments for both AUCinf and Cmax is 0.95 and also assumes within-participant SDs of 0.141 
and 0.246 for ln(AUCinf) and ln(Cmax) of spironolactone and 0.165 and 0.179 for ln(AUCinf)
and ln(Cmax) of hydrochlorothiazide, respectively, as obtained from the literature (Xu et al, 
2008; Fierro Humberto, 2016).
Approximately 40 participants will be enrolled in the study (20 in each treatment sequence) 
to ensure at least 38 evaluable participants. Participants who withdraw from the study or 
discontinue treatment, or whose PK samples are considered to be non-evaluable with respect 
to the primary PK objective may be replaced at the discretion of the investigator upon 
consultation with the sponsor.


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant or their legally authorized representative
and answer all questions regarding the study. The participant or their legally authorized 
representative should be given sufficient time and opportunity to ask questions and to decide 
whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative (if allowed by local regulations) will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, privacy and data protection requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each participant or their legally authorized representative is 
fully informed about the nature and objectives of the study, the sharing of data related to the 
study, and possible risks associated with participation, including the risks associated with the 
processing of the participant’s personal data. 
The participant or their legally authorized representative must be informed that their personal 
study-related data will be used by the sponsor in accordance with local data protection law. 
The level of disclosure must also be explained to the participant or their legally authorized 
representative.
The participant or their legally authorized representative must be informed that their medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/EC members, and by inspectors 
from regulatory authorities.
The investigator further must ensure that each study participant or their legally authorized 
representative is fully informed about their right to access and correct their personal data and 
to withdraw consent for the processing of their personal data.


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The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants or their legally authorized representative must be reconsented to the most current 
version of the IRB/EC-approved ICD(s) during their participation in the study as required per 
local regulations.
A copy of the ICD(s) must be provided to the participant or their legally authorized 
representative (if allowed by local regulations).
Participants who are rescreened are required to sign a new ICD.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic form and 
will be password protected to ensure that only authorized study staff have access. The study 
site will implement appropriate technical and organizational measures to ensure that the 
personal data can be recovered in the event of disaster. In the event of a potential personal 
data breach, the study site will be responsible for determining whether a personal data breach 
has in fact occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
10.1.5. Committees Structure
Not applicable.
10.1.5.1. Data Monitoring Committee 
This study will not use an E-DMC.


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10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.


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Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password-protected to prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source records and documents.
This verification may also occur after study completion. It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality, such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan maintained 
and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 


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with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes a source document and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source record) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Use of Medical Records
There may be instances when copies of medical records for certain cases are requested by 
Pfizer Safety, where ethically and scientifically justified and permitted by local regulations, 
to ensure participant safety.
Due to the potential for a participant to be re-identified from their medical records, the 
following actions must be taken when medical records are sent to the sponsor or sponsor 
designee:

The investigator or site staff must redact personal information from the medical 
record. The personal information includes, but is not limited to, the following: 
participant names or initials, participant dates (eg, birth date, date of hospital 
admission/discharge, date of death), participant identification numbers (eg, Social 
Security number, health insurance number, medical record number, 


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hospital/institution identifier), participant location information (eg, street address, 
city, country, postal code, IP address), participant contact information (eg, 
telephone/fax number, email address).

Each medical record must be transmitted to the sponsor or sponsor designee using 
systems with technical and organizational security measures to ensure the protection 
of personal data (eg, Florence is the preferred system if available).
There may be unplanned situations where the sponsor may request medical records (eg, 
sharing medical records so that the sponsor can provide study-related advice to the 
investigator). The medical records should be submitted according to the procedure described 
above.
10.1.10. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.


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10.1.11. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results. For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
10.1.12. Sponsor’s Medically Qualified Individual
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the supporting study documentation/study portal or other electronic 
system.
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from non-study healthcare professionals, participants are provided 
with an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol 
and study intervention identifiers, (b) participant’s study identification number, (c) site 
emergency phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center 
number.


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The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. The Pfizer Call Center number is to be used when the investigator and site staff 
are unavailable. The Pfizer Call Center number is not for use by the participant directly; if a 
participant calls that number directly, they will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values; for example: calculation of estimated kidney function. These 
additional tests would not require additional collection of blood. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
Table 5.
Protocol-Required Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
Urea
Creatinine
Cystatin Ca
eGFR
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Local dipstick:
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Laboratory:
Microscopy and 
cultureb
At screening:

FSHc

Urine drug screeningd

Hepatitis B surface 
antigen

HBcAb

Hepatitis C antibody

HIV
Pregnancy test (β-hCG)e
a.
Cystatin C (Scys): Screening or Baseline Scys is recommended to help differentiate post-baseline DIKI 
from DICI. Post-baseline, Scys is measured if and only if serum creatinine increase post-baseline is observed 
(see Section 7.1.1).
b.
Only if UTI is suspected and urine dipstick is positive for nitrites or leukocyte esterase or both.
c.
For confirmation of postmenopausal status only in females <60 years old and not using hormonal or 
HRT only.
d.
The minimum requirement for drug screening includes cocaine, THC, marijuana, opiates/opioids, 
benzodiazepines, and amphetamines (others are site- and study-specific).
e.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/EC. See SoA for collection times.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abnormal test results that meet any of the conditions below must be recorded as 
an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration,
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d. Results in persistent or significant disability/incapacity


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
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic 
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs using the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must 
be completed in a consistent manner. AEs should be recorded using concise medical 


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terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding
All AEs/SAEs associated 
with EDP or EDB
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not
there is an associated 
SAE)**
Environmental or 
occupational exposure 
to the product under 
study to a 
nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
non-participant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
EDP (with or without an associated SAE): is reported to Pfizer Safety using the CT SAE Report 
Form and EDP Supplemental Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, which would also include 
details of any SAE that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form

When an AE or SAE occurs, it is the responsibility of the investigator to review 
all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 


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records before submission to Pfizer Safety. Refer to Section 10.1.9 for actions that 
must be taken when medical records are sent to the sponsor or sponsor designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:

Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual ADL.

Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant.

Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for 
marketed products, in their assessment.


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
For each AE or SAE, the investigator must document in the medical notes that 
they have reviewed the AE or SAE and have provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor.

The investigator may change their opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor. In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 
24 hours of receipt of the information.


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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT (eg, eSAE or PSSA).

If the electronic system is unavailable, then the site will use the paper SAE report 
form (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic DCT has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via the CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is one of the methods to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.


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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 4 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s):

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a longterm and persistent basis) and agree to remain abstinent. 
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom, and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception, as a condom 
may break or leak when having sexual intercourse with a WOCBP who is not 
currently pregnant.

In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study.
A female participant is eligible to participate if she is not pregnant or breastfeeding and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definition in Section 10.4.3).
OR

Is a WOCBP and agrees to use a highly effective contraceptive method (failure rate of 
<1% per year) during the intervention period and for at least 4 days after the last dose 
of study intervention, which corresponds to the time needed to eliminate any 
reproductive safety risk of the study intervention(s). If a highly effective, 
user-dependent method is chosen, she agrees to concurrently use an effective barrier 


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method of contraception. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea or oligomenorrhea) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied 
to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT.

A female on HRT and whose menopausal status is in doubt will be required to 
use one of the highly effective nonestrogen hormonal contraception methods 
if she wishes to continue her HRT during the study. Otherwise, she must 


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discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral + barrier*

Intravaginal + barrier*

Transdermal + barrier*
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral + barrier*

Injectable + barrier*


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Sexual Abstinence
8. Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following:

Male or female condom, with or without spermicide;

Cervical cap, diaphragm or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge 
with spermicide (double-barrier methods).
10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to Spironolactone/Hydrochlorothiazide or study interventions 
of this class to understand treatments for the disease(s) under study or the disease(s) 
themselves.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.

The samples will be retained as indicated:

Retained samples will be stored indefinitely or for another period as per local 
requirements.

Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, any 


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remaining material will be destroyed. Data already generated from the samples will be 
retained to protect the integrity of existing analyses.

Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site.


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
LFTs are not required as a routine safety monitoring procedure in this study. However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described 
below.
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to T bili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value ≥2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available.

For participants with baseline AST OR ALT OR T bili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller).


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
Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, eosinophils (%), and alkaline phosphatase. Consideration should also be
given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology. A detailed history, including relevant information, 
such as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, total bile acids, liver imaging (eg, biliary tract), and 
collection of serum samples for acetaminophen/paracetamol drug and/or protein adduct 
levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.7. Appendix 7: Kidney Safety: Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline Screat 
measurement to estimate kidney function [Screat-based eGFR]). Obtaining Screening or 
Baseline Scys and postbaseline reflex Scys (if confirmed Screat increase ≥0.3 mg/dL) makes 
it feasible to distinguish AKI from DICI. If Screat increase is confirmed after baseline, then 
reflex measurement of Scys is indicated:
ADULTS: Currently, 2021 CKD-EPI eGFR equations (Screat-only based and combined 
Screat plus Scys-based) are valid for use in adults only. At baseline Screat and Scys values 
are needed to calculate 2021 CKD-EPI eGFR by Screat-only based equation (see Table in 
Section 10.7.2.1) and by combined Screat plus Scys-based equation. When post-baseline 
Screat increase ≥0.3 mg/dL is confirmed, then reflex Scys measurement is needed to enable 
post-baseline comparison of eGFR changes (Screat-only based eGFR and combined Screat 
plus Scys eGFR).
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care.
10.7.2. Age-Specific Kidney Function Calculation Recommendations
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
eGFR (mL/min/1.73m²) (Inker et al, 2021)
2021 
CKD-EPI
Screat Only
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
NA
eGFR = 143 × (Screat/0.7)-0.241 × (0.9938)Age
Female
if > 0.7
NA
eGFR = 143 × (Screat/0.7)-1.200 × (0.9938)Age
Male
if ≤ 0.9
NA
eGFR = 142 × (Screat/0.9)-0.302 × (0.9938)Age
Male
if > 0.9
NA
eGFR = 142 × (Screat/0.9)-1.200 × (0.9938)Age
2021 
CKD-EPI 
Screat-Scys 
Combined
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
if ≤ 0.8
eGFR = 130 × (Screat/0.7)-0.219 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if ≤ 0.7
if > 0.8
eGFR = 130 × (Screat/0.7)-0.219 × (Scys/0.8)-0.778 × (0.9961)Age
Female
if > 0.7
if ≤ 0.8
eGFR = 130 × (Screat/0.7)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if > 0.7
if > 0.8
eGFR = 130 × (Screat/0.7)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if ≤ 0.9
if ≤ 0.8
eGFR = 135 × (Screat/0.9)-0.144 × (Scys/0.8)-0.323 × (0.9961)Age
Male
if ≤ 0.9
if > 0.8
eGFR = 135 × (Screat/0.9)-0.144 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if > 0.9
if ≤ 0.8
eGFR = 135 × (Screat/0.9)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
Male
if > 0.9
if > 0.8
eGFR = 135 × (Screat/0.9)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age


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10.7.3. Kidney Function Calculation Tools
The sponsor has provided the following resources to investigational sites when required to 
calculate age-specific kidney function at Screening, Baseline, and post-Baseline visits. Site 
calculations of kidney function can be performed manually, using the age appropriate 
formulae (see Section 10.7.2) and can use recommended online kidney function calculators 
to reduce the likelihood of a calculation error. 
The United States National Kidney Foundation Online Calculators. 

Adults (18 years and above) - 2021 CKD-EPI Creatinine Online Calculator (eGFR): 
https://www.kidney.org/professionals/KDOQI/gfr_calculator
Investigational sites are responsible to ensure that the accurate age-specific equation is 
selected and that the correct units are used for serum creatinine (mg/dL only), serum 
cystatin C (mg/L only), total body weight (kg only), and age (years). Investigators are 
expected to (i) review and confirm correctness of the kidney function calculation results and 
(ii) evaluate the calculated value within the context of historical information available to 
them in the participant’s medical record. Investigators are responsible for the clinical 
oversight of the participant eligibility process, kidney function calculation, and dose selection 
and adjustments per study protocol. Investigators are encouraged to direct questions or 
uncertainties regarding kidney function and dosing to the Pfizer Clinical Team and Medical 
Monitor, if needed.
10.7.4. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR) will be according to Kidney Disease: 
Improving Global Outcomes (KDIGO) criteria for adult participants.
KDIGO criteria 
grade (G)
Study 
Population
G1
G2
G3
G4
G5
Decreased Kidney 
Function due to 
either Acute or 
Chronic Kidney 
Injury
Adult 
participants
eGFR 
(mL/min/1.73m²)
≥90 
≥60 to 89
30 to 59 
15 to 29
<15
KDIGO albuminuria (A) criteria
A1
A2
A3
Albumin-to-creatinine ratio (ACR)
<30 mg/g
OR
<3 mg/mmol 
30 to 300 mg/g
OR
3 to 30 mg/mmol
>300 mg/g
OR
>30 mg/mmol


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10.8. Appendix 8: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 ms.

New prolongation of QTcF to >480 ms (absolute).

New prolongation of QTcF by >60 ms from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30-second duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 ms.

Absolute value of QTcF > 450 ms AND QTcF change from baseline >60 ms.

New ST-T changes suggestive of myocardial ischemia.

New-onset LBBB (QRS complex>120 ms).

New-onset right bundle branch block (QRS complex>120 ms).

Symptomatic bradycardia.

Asystole

In awake, symptom-free participants in sinus rhythm, with documented 
asystolic pauses ≥3 seconds or any escape rate <40 bpm, or with an escape 
rhythm that is below the AV node;

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more asystolic pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.


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
Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 second duration, including idioventricular rhythm (HR
<40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as
torsades de pointes]).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30-seconds duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The major events of potential clinical concern listed above are recommended as “alerts” or notifications 
from the core ECG laboratory to the investigator and Pfizer study team, and not to be considered as all-
inclusive of what is to reported as AEs/SAEs.


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10.9. Appendix 9: Prohibited Concomitant Medications That May Result in DDI
The prohibited concomitant medications listed below should not be taken with 
Spironolactone/Hydrochlorothiazide for the period of time at least equal to, the required 
washout period listed in the table, and throughout the conduct of the study.
The Pfizer study team is to be notified of any prohibited medications taken during the study. 
After consulting with the sponsor, the investigator will make a judgment on the ongoing 
participation of any participant with prohibited medication use during the study.
This list of drugs prohibited for potential DDI concerns with the IMP may be revised during 
the course of the study with written notification from the sponsor to include or exclude 
specific drugs or drug categories for various reasons (eg, emerging DDI results for the IMP, 
availability of new information in literature on the DDI potential of other drugs) if the overall
benefit/risk assessment is not impacted or if the changes do not significantly impact the 
safety of participants or the scientific value of the trial.
This is not an all-inclusive list. Site staff should consult with the sponsor or designee with 
any questions regarding potential DDI.
Drug Category
Drugs
Required Washout Period Requirement
ACE inhibitors
Benazepril, Captopril, 
Enalapril, Fosinopril, 
Lisinopril, Moexipril, 
Perindopril, Quinapril, 
Ramipril, Trandolapril
5 days
or
5 half-lives
whichever is longer
Angiotensin II Receptor 
antagonists
Losartan, telmisartan, 
irbesartan, Olmesartan, 
valsartan
5 days
or
5 half-lives
whichever is longer
Aldosterone blockers
Eplerenone, Finerenone
3 days
or
5 half-lives
whichever is longer
Potassium supplements
Potassium iodide, Potassium 
chloride
5 days
or
5 half-lives
whichever is longer
Anticoagulants
Heparin, low molecular 
weight heparin
8 hours
or
5 half-lives
whichever is longer
Alcohol
Ethyl alcohol
1 day
or
5 half-lives
whichever is longer
Antidiabetic drugs
Insulin, sulphonylureas, 
Biguanides, meglitinides, 
thiazolidinediones, Alpha 
glucosidase inhibitors
2 weeks
or
5 half-lives
whichever is longer


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Drug Category
Drugs
Required Washout Period Requirement
Corticosteriods, ACTH
Hydrocortisone, 
Dexamethasone, 
methylprednisone and 
prednisone
1 day
or
5 half-lives
whichever is longer
Pressor amines
Norepinephrine, 
phenylephrine, ephidrine
1.5 days
or
5 half-lives
whichever is longer
Skeletal muscle relaxants, 
nondepolarizing
Tubocuraine
10 hours
or
5 half-lives
whichever is longer
Antimaniac/Antidepressant
lithium
5 days
or
5 half-lives
whichever is longer
NSAIDs
Indomethacin, Dyclofenac, 
Aceclofenac, ibuprofen, 
naproxen, aspirin, 
acetylsalicylic acid
1 day
or
5 half-lives
whichever is longer
Cardiac glycoside
Digoxin
2 weeks
or
5 half-lives
whichever is longer
Bile acid sequestrant
Cholestyramine
5 hours
or
5 half-lives
whichever is longer
Androgen biosynthesis 
inhibitor
Abiraterone
3.5 days
or
5 half-lives
whichever is longer
Investigators should consult the USPIs for Spironolactone/Hydrochlorothiazide for
information regarding medication that is prohibited for concomitant use.
Investigators should consult the product label for any other medication used during the study 
for information regarding medication that is prohibited for concomitant use.


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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
A1 to A3
albuminuria (KDIGO albuminuria severity standardization)
Abs
absolute
ACE
angiotensin-converting enzyme
ACR
albumin-to-creatinine ratio
ACTH
adrenocorticotropic hormone
ADL
activity/activities of daily living
AE
adverse event
AESI
adverse event of special interest
AKI
acute kidney injury
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUCinf
area under the plasma concentration-time profile from time 0 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time 0 to the 
time of the last quantifiable concentration (Clast)
AV
atrioventricular
AxMP
auxiliary medicinal product
BA
bioavailability
BE
bioequivalence
β-hCG
-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
bpm
beats per minute
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology
Clast
the last quantifiable concentration
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
CTIS
Clinical Trial Information System


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Abbreviation
Term
DCT
data collection tool
DDI
drug-drug interaction 
DICI
drug-induced creatinine increase
DIKI
drug-induced kidney injury
DILI
drug-induced liver injury
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram or electrocardiography
eCRF
electronic case report form
EDB
exposure during breastfeeding
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
eSAE
electronic serious adverse event
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
f2
degree of similarity
FSH
follicle-stimulating hormone
F/U
follow-up
G1 to G5
Grade (KDIGO eGFR category standardization)
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCTZ
Hydrochlorothiazide
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
IPAL
Investigational Product Accountability Log
IPM
investigational product manual
IRB
Institutional Review Board
KDIGO
Kidney Disease Improving Global Outcomes


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Abbreviation
Term
kel
first-order elimination rate constant
LBBB
left bundle branch block
LFT
liver function test
MQI
medically qualified individual
NA
not applicable
NDA
New Drug Application
NIMP
noninvestigational medicinal product
NSAID
Non-Steroidal Anti-Inflammatory Drug
PD
pharmacodynamic(s)
PGS
Pfizer Global Supply
PR
pulse rate
PK
pharmacokinetic(s)
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT
prothrombin time
PVC
premature ventricular contraction/complex
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
RSD
relative standard deviation
SAE
serious adverse event
SAP
Statistical Analysis Plan
Screat
serum creatinine 
Scys
serum cystatin C
SoA
schedule of activities
SOP
standard operating procedure
SRSD
Single Reference Safety Document
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal elimination half-life
T bili
total bilirubin
THC
tetrahydrocannabinol
Tmax
time for Cmax
ULN
upper limit of normal
US
United States
USPI
United States Prescribing Information
UTI
urinary tract infection
WBC
white blood cell
WOCBP
woman/women of childbearing potential


PF-06832640
Protocol B9531002
Final Protocol, 28 September 2023
PFIZER CONFIDENTIAL
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Page 86
11. REFERENCES
CDS. Spironolactone/Thiazide Core Data Sheet (CDS). 14 April 2022(Version 12.0).
Fierro Humberto RR, Yáñez Sebastian, Acuña Paola, Rosales Katherine, Yevenes Paulina, 
Yzoard Marcia, Tapia Claudia, Rivas Violeta, Caba Alvaro, Copaja Miguel, Jorge 
Fuentealba. Bioequivalence Study of Two Hydrochlorothiazide Formulations after Oral 
Administration in Healthy Chilean Volunteers. Journal of Pharmacy and Pharmacology (El 
Monte). 2016;4(12):679-85.
Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based Equations to 
Estimate GFR without Race. N Engl J Med. 2021;385(19):1737-49.
Spironolactone and Hydrochlorothiazide Tablet, US Prescription Information (USPI) 
[Internet]. Prasco Laboratories. 09 January 2023 [cited 18 Aug 2023]. Available from: 
https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=9d350fa2-d568-4970-
a7a5-d128ff5d0a2f&type=display.
Xu FG, Zhang ZJ, Dong HJ, et al. Bioequivalence assessment of two formulations of 
spironolactone in Chinese healthy male volunteers. Arzneimittelforschung. 2008;58(3):117-
21.

SAP_001.pdf: 
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Protocol B9531002
A single-dose, open-label, randomized, 2-way, cross-over pivotal bioequivalence 
study to qualify manufacturing site transfer from Viatris to Neolpharma, for
Spironolactone/Hydrochlorothiazide film coated tablets in healthy adult participants 
under fasted conditions
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
17 Nov 2023


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TABLE OF CONTENTS
LIST OF TABLES..................................................................................................................3
APPENDICES.......................................................................................................................3
1. VERSION HISTORY .........................................................................................................4
2. INTRODUCTION...............................................................................................................4
2.1. Modifications to the Analysis Plan Described in the Protocol.................................4
2.2. Study Objectives, Endpoints, and Estimands ........................................................4
2.3. Study Design.........................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND CONVENTIONS ..........5
3.1. Primary Endpoints.................................................................................................5
3.2. Secondary Endpoints ............................................................................................6
3.2.1. Other PK parameters ................................................................................6
3.2.2. Safety endpoints .......................................................................................6
3.2.2.1. Adverse Events........................................................................6
3.2.2.2. Laboratory Data .......................................................................7
3.2.2.3. Vital Signs................................................................................7
3.2.2.4. Electrocardiograms ..................................................................7
3.3. Other Safety Endpoint(s).......................................................................................7
3.4. Exploratory Endpoints ...........................................................................................7
3.5. Baseline Variables ................................................................................................7
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) .......................................................7
5. GENERAL METHODOLOGY AND CONVENTIONS.........................................................8
5.1. Hypotheses and Decision Rules............................................................................8
5.2. General Methods...................................................................................................8
5.2.1. Analyses for Binary/Categorical Endpoints................................................8
5.2.2. Analyses for Continuous Endpoints...........................................................8
5.3. Methods to Manage Missing Data.........................................................................9
5.3.1. Pharmacokinetic Data...............................................................................9
5.3.2. Safety Data...............................................................................................9
6. ANALYSES AND SUMMARIES ......................................................................................10
6.1. Primary Endpoints...............................................................................................10
6.2. Secondary Endpoints ..........................................................................................11
6.2.1. Other PK parameters ..............................................................................11
6.2.2. Safety endpoints .....................................................................................11


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6.2.2.1. Adverse Events......................................................................11
6.2.2.2. Laboratory Data .....................................................................11
6.2.2.3. Vital Signs..............................................................................11
6.2.2.4. Electrocardiograms ................................................................11
6.3. Other Safety Summaries and Analyses Endpoint(s)............................................12
6.4. Exploratory Endpoints .........................................................................................12
6.5. Subset Analyses .................................................................................................12
6.6. Baseline and Other Summaries and Analyses ....................................................12
6.6.1. Demographic Summaries........................................................................12
6.6.2. Study Conduct and Participant Disposition..............................................12
6.6.3. Study Treatment Exposure .....................................................................12
6.6.4. Concomitant Medications and Nondrug Treatments................................12
7. INTERIM ANALYSES......................................................................................................12
APPENDICES.....................................................................................................................13
LIST OF TABLES
Table 1.
Summary of Changes..............................................................................4
Table 2.
Treatment Sequence...............................................................................5
Table 3.
Plasma PK Parameters Definitions..........................................................6
Table 4.
PK Parameters to be Summarized Descriptively ...................................10
APPENDICES
Appendix 1. Summary of Analyses......................................................................................13
Appendix 2. SAS Code for Analyses ...................................................................................13
Appendix 3. List of Abbreviations ........................................................................................14


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NOTE: Italicized text within this document has been taken verbatim from the Protocol.
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1 /
17 Nov 2023
Original
28 Sep 2023
N/A
N/A
2. INTRODUCTION
Spironolactone/Hydrochlorothiazide film coated tablets are a combination of 2 diuretic
agents spironolactone and hydrochlorothiazide indicated for treatment of essential
hypertension, congestive heart failure, liver cirrhosis, nephrotic syndrome and other
edematous conditions. Spironolactone and hydrochlorothiazide have different but
complementary mechanisms and sites of action, thereby providing additive diuretic and
antihypertensive effects.
The purpose of this study is to assess the bioequivalence (BE) between
Spironolactone/Hydrochlorothiazide film coated tablets manufactured at Viatris and
Spironolactone/Hydrochlorothiazide film coated tablets manufactured at Neolpharma.
This SAP provides the detailed methodology for summary and statistical analyses of the 
data collected in Study B9531002. 
2.1. Modifications to the Analysis Plan Described in the Protocol
None.
2.2. Study Objectives, Endpoints, and Estimands
The following are the objectives and endpoints in this study. Estimand framework will not be 
applied to this Phase 1 study in healthy participants.


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Objectives
Endpoints
Primary: 
Primary:

To demonstrate bioequivalence between 
Spironolactone/Hydrochlorothiazide 25 
mg/25 mg film coated tablets manufactured 
at the proposed site (Neolpharma) vs 
Spironolactone/Hydrochlorothiazide 25 
mg/25 mg film coated tablets manufactured 
at current site (Viatris) under fasting 
conditions in healthy adult participants.
Cmax, AUCinf (or AUClast if AUCinf cannot be 
reliably estimated) of Spironolactone and 
Hydrochlorothiazide.
Secondary: 
Secondary:

To further characterize PK of 
Spironolactone and Hydrochlorothiazide.

To evaluate the safety and tolerability of 
Spironolactone/Hydrochlorothiazide film 
coated tablets.
t½ (if data permit) and Tmax of Spironolactone 
and Hydrochlorothiazide.
AEs, clinical laboratory tests, vital signs, and 
ECGs. 
2.3. Study Design
This will be an open-label, randomized, single-dose, 2-treatment, 2-period, 2-sequence,
crossover study in adult healthy male and/or female participants. Approximately 40 
participants will be enrolled in the study (20 in each treatment sequence). Dropouts for non-
safety reasons or non-evaluable participants may be replaced at the discretion of the
sponsor and investigator. Screening evaluation will occur within 28 days prior to the first 
dose of study medication. Participants will be assigned to 1 of the following 2 sequences
according to a computer-generated randomization schedule.
Table 2.
Treatment Sequence
Sequence
Number of 
Participants
Period 1
Washout Period
Period 2
1
20
Treatment A
At least 4 days
Treatment B
2
20
Treatment B
Treatment A
Treatment A: Spironolactone/Hydrochlorothiazide 25 mg/25 mg film coated tablets manufactured at the 
current site (Viatris) under fasting conditions.
Treatment B: Spironolactone/Hydrochlorothiazide 25 mg/25 mg film coated tablets manufactured at the 
proposed site (Neolpharma) under fasting conditions.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND CONVENTIONS
3.1. Primary Endpoints
The primary endpoints of the study are plasma Cmax, AUCinf (or AUClast if AUCinf cannot be 
reliably estimated) of Spironolactone and Hydrochlorothiazide. Adjusted geometric mean 
ratios of Cmax, AUCinf and AUClast will be derived.
PK parameters will be derived from the concentration-time profiles as shown in Table 3.
Actual PK sampling times will be used in the derivation of PK parameters. In the case that 


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actual PK sampling times are not available, nominal PK sampling time will be used in the 
derivation of PK parameters.
Table 3.
Plasma PK Parameters Definitions
Parameter
Definition
Method of Determination
AUClast
Area under the plasma 
concentration-time profile from time 
0 to time of the last quantifiable 
concentration (Clast)
Linear-log trapezoidal rule
AUCinfa
Area under the plasma 
concentration-time profile from time 
0 extrapolated to infinite time
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable time 
point estimated from the log-linear regression 
analysis.
Cmax
Maximum plasma concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
t½a
Terminal elimination half-life
Ln(2)/kel,
where kel is the terminal phase rate constant 
calculated by a linear regression of the 
log-linear concentration-time curve. Only 
those data points judged to describe the 
terminal log-linear decline will be used in the 
regression
a.
If data permits.
3.2. Secondary Endpoints
3.2.1. Other PK parameters
Other PK parameters of Spironolactone and Hydrochlorothiazide, including t1/2 (if data 
permit) and Tmax will be derived.
3.2.2. Safety endpoints
The following data will be considered in standard safety summaries (see protocol for 
collection days, baseline assessment, and list of parameters): 

Adverse events (AE)

Laboratory data

Vital signs data

ECG results
3.2.2.1. Adverse Events
Any adverse events occurring following start of treatment will be considered as treatment 
emergent adverse event (TEAE). Events that occur during follow-up within the lag time of up 
to 35 days after the study drug dose will be counted as treatment emergent and attributed to 
the last treatment taken. Events that occur during the washout period between study periods 
will be counted as treatment emergent and attributed to the previous treatment taken. The 


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time period for collecting AEs (“active collection period”) for each participant begins from the 
time the participant provides informed consent. 
3.2.2.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol. 
The baseline measurement is the last predose measurement prior to administration of study 
drug in Period 1.
3.2.2.3. Vital Signs
Supine blood pressure (BP) and pulse rate (PR) will be measured at times specified in the 
SoA given in the protocol.
The baseline measurement is the last predose measurement prior to administration of study 
drug in Period 1.
3.2.2.4. Electrocardiograms
QT interval, QTcF, PR, QRS and heart rate (HR) will be recorded at each assessment time 
indicated in the SoA given in the protocol. If not supplied, QTcF will be derived using 
Fridericia’s heart rate correction formula:
QTcF = QT / (RR)^(1/3) where RR = 60/HR (if not provided)
The baseline value is the last predose measurement on prior to administration of study drug 
in Period 1.
3.3. Other Safety Endpoint(s)
None.
3.4. Exploratory Endpoints
None.
3.5. Baseline Variables
Baseline characteristics will be collected according to the SoA as specified in the protocol. 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures.
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled 
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
randomization.


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Participant Analysis Set
Description
Full analysis set
All participants randomly assigned to study intervention and who 
take at least 1 dose of study intervention.
Safety analysis set
All participants randomly assigned to study intervention and who 
take at least 1 dose of study intervention. Participants will be 
analyzed according to the product they actually received.
PK Concentration Set
All participants who take at least 1 dose of study intervention
and in whom at least 1 concentration value is reported.
PK Parameter Set
All participants who take at least 1 dose of study intervention
and in whom at least 1 of the PK parameters of primary interest are 
reported.
5. GENERAL METHODOLOGY AND CONVENTIONS
Final analysis will be performed after study participant data set release following last 
participant last visit.
5.1. Hypotheses and Decision Rules
The alternative hypothesis of BE (H1: L T - R U), and the null hypothesis of
inequivalence (Ho: T - R LorT - R U) can be expressed as the following 2 separate
1-sided hypotheses:
HoA: T - R L
H1A: LT - R
HoB: T - R U
H1B: T - R U
Where T and R represent the average BA on a log scale for the Test and Reference
products respectively and [L, U] defines the BE range.
BE of the Test treatment to Reference treatment will be concluded if the 90% CIs for the
ratios of adjusted geometric means for both spironolactone and hydrochlorothiazide AUCinf
and Cmax fall entirely within the acceptance region of (80%, 125%).
5.2. General Methods
5.2.1. Analyses for Binary/Categorical Endpoints
For binary or categorical variables, number of participants, numbers and percentages of 
participants meeting the categorical criteria will be presented in accordance with the Clinical 
Data Interchange Standards Consortium and Pfizer Standards (CaPS).
5.2.2. Analyses for Continuous Endpoints
For continuous variables, the data will be summarized using the number of participants, 
mean, median, standard deviation (SD), minimum, and maximum in accordance with the 
CaPS. For appropriate PK parameters, geometric mean and geometric coefficient of 
variation (%CV) will also be summarized.


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5.3. Methods to Manage Missing Data
5.3.1. Pharmacokinetic Data
Methods to handle missing PK data are described below. 
Concentrations Below the Limit of Quantification:
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. (In listings BLQ values will be reported as “<LLQ”, where LLQ will 
be replaced with the value for the lower limit of quantification.).
Deviations, Missing Concentrations and Anomalous Values:
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if one of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample).
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other 
participants. For example, a BLQ concentration that is between quantifiable values from the 
same dose is considered as anomalous. Anomalous concentration values may be excluded 
from PK analysis at the discretion of the PK analyst or pharmacokineticist.
PK Parameters:
Actual PK sampling times will be used in the derivation of PK parameters. If a PK parameter 
cannot be derived from a participant’s concentration data, the parameter will be coded as 
NC (ie, not calculated). (Note that NC values will not be generated beyond the day that a 
participant discontinues). In summary tables, statistics will be calculated by setting NC 
values to missing; and statistics will be presented for a particular treatment with ≥3 
evaluable measurements. PK parameter analyses will not be performed for a particular 
parameter if more than 50% of the data are NC.
If an individual participant has a known biased estimate of a PK parameter (due for example 
to an unexpected event such as vomiting before all the compound is adequately absorbed 
from the gastrointestinal tract), this will be footnoted in summary tables and will not be 
included in the calculation of summary statistics or statistical analyses.
5.3.2. Safety Data
For the analysis of safety endpoints, the standard rules for imputation according to CaPS
will be applied.


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6. ANALYSES AND SUMMARIES
6.1. Primary Endpoints
The primary endpoints Cmax and AUCinf (if data permits, otherwise AUClast) will be 
summarized descriptively by treatment and will include the set of summary statistics as 
specified in Table 4. Box and whisker plots for individual participant parameters (Cmax, AUCinf
and AUClast) will be plotted by treatment and overlaid with geometric means.
Natural log transformed PK parameters (Cmax, AUCinf (or AUClast if AUCinf cannot be reliably 
estimated)) will be analyzed using a mixed effect model with sequence, period and 
treatment as fixed effects and participant within sequence as a random effect. Estimates of 
the adjusted mean differences (Test-Reference) and the corresponding 90% CIs will be 
obtained from the model. The adjusted mean differences and the 90% CIs for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and the 90% CIs for the ratios.
For bioequivalence assessment of Spironolactone/Hydrochlorothiazide 25/25 mg film coated 
tablets between proposed site (Neolpharma) and current site (Viatris), bioequivalence of the 
Test treatment (Treatment B) relative to Reference treatment (Treatment A) will be 
concluded if the 90% confidence intervals for the ratio of adjusted geometric means of Test 
treatment (Treatment B) relative to Reference treatment (Treatment A) for Cmax, AUCinf (or 
AUClast if AUCinf cannot be reliably estimated) fall wholly within (80%, 125%).
PK parameters will be summarized descriptively in accordance with Pfizer data standards 
for the PK Parameter Set, as data permit. Missing values will be handled as detailed in 
Section 5.3.1. Each PK parameter will be summarized and will include the set of summary 
statistics as specified in Table 4.
Table 4.
PK Parameters to be Summarized Descriptively 
Parameter
Summary Statistics
AUCinf, AUClast, Cmax
N, arithmetic mean, median, SD, %CV, minimum, 
maximum, geometric mean and geometric %CV
Tmax
N, median, minimum, maximum
t½
N, arithmetic mean, median, SD, %CV, minimum, 
maximum
Supporting data from the estimation of t½ and AUCinf will be listed by analyte and group: 
terminal phase rate constant (kel); goodness of fit statistic from the log-linear regression (r2); 
the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of 
time points used in the estimation of kel. This data may be included in the clinical study 
report.
Presentations for plasma concentrations using the PK Concentration Set will include:

A listing of all concentrations sorted by participant ID, treatment and nominal time 
postdose. The concentration listing will also include the actual times. Deviations from the 
nominal time will be provided in a separate listing.


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
A summary of concentrations by treatment and nominal time postdose, where the set of 
statistics will include n, mean, median, SD, %CV, minimum, maximum and the number 
of concentrations above the LLQ.

Median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose).

Mean concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose).

Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment 
per scale).

Individual concentration time plots by participant (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each participant (containing 
all treatments) per scale].
6.2. Secondary Endpoints
6.2.1. Other PK parameters
Other PK parameters including Tmax and t1/2 will be summarized descriptively by treatment 
and will include the set of summary statistics as specified in Table 4.
6.2.2. Safety endpoints
All safety analyses will be performed on the Safety Analysis Set.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively by treatment, where appropriate.
6.2.2.1. Adverse Events
Adverse events will be reported in accordance with the CaPS and listed by treatment, where 
appropriate.
Participant discontinuations due to adverse events will be detailed by treatment. Data will be 
reported in accordance with the CaPS.
6.2.2.2. Laboratory Data
Laboratory data will be listed by treatment in accordance with the CaPS.
6.2.2.3. Vital Signs
Vital signs data will be databased and available upon request.
6.2.2.4. Electrocardiograms
ECG data will be databased and available upon request.


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6.3. Other Safety Summaries and Analyses Endpoint(s)
None.
6.4. Exploratory Endpoints
None.
6.5. Subset Analyses
There are no planned subset analyses.
6.6. Baseline and Other Summaries and Analyses
6.6.1. Demographic Summaries
Demographic characteristics will be summarized for safety population in accordance with the 
CaPS.
6.6.2. Study Conduct and Participant Disposition
Participants evaluation groups will show end of study participant disposition. Frequency 
counts will be supplied for participant discontinuation(s) by treatment. Data will be reported 
in accordance with the CaPS.
6.6.3. Study Treatment Exposure
Study treatment exposure will be listed.
6.6.4. Concomitant Medications and Nondrug Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be reported in the 
listings.
7. INTERIM ANALYSES
No interim analysis will be conducted for this study. As this is an open-label study, the 
sponsor may conduct reviews of the data during the course of the study for the purpose of 
safety assessment, facilitating PK modeling, and/or supporting clinical development.


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APPENDICES
Appendix 1. Summary of Analyses
Endpoint
Population
Data Inclusion and Rules for 
Handling Intercurrent 
Events and Missing Data 
Analysis 
Method
Geometric mean ratio of 
Cmax, AUCinf, AUClast
PK Parameter 
Analysis Set
Observed and imputed 
(Section 5.3.1) data
Mixed effect 
model
PK parameters
PK Parameter 
Analysis Set
Observed and imputed 
(Section 5.3.1) data
Descriptive 
statistics
PK concentrations
PK Concentration 
Analysis Set
Observed and imputed 
(Section 5.3.1) data
Descriptive 
statistics
Safety endpoints
Safety Analysis Set
Observed and imputed 
(Section 5.3.2) data 
Descriptive 
statistics
Appendix 2. SAS Code for Analyses
An example of PROC MIXED code is provided below.
For bioequivalence:
proc mixed data=tab.pk;
class seq period trt participant;
model log&var=sequence period trt / ddfm=KR;
random participant(seq) / subject=participant(seq);
lsmeans trt;
estimate 'B vs A' trt -1 1 /cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
/* Letter assignments for treatments (trt) within the estimate statement above are as follows
A: Spironolactone/Hydrochlorothiazide 25 mg/25 mg film coated tablets manufactured at the
current site (Viatris) under fasting conditions.
B: Spironolactone/Hydrochlorothiazide 25 mg/25 mg film coated tablets manufactured at the
proposed site (Neolpharma) under fasting conditions.
*/


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Appendix 3. List of Abbreviations
Abbreviation
Term
%CV
coefficient of variation
AE
adverse event
AUCextrap%
the percent of AUCinf based on extrapolation
AUCinf
area under the plasma concentration-time profile from time zero 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time zero to the time 
of the last quantifiable concentration
BE
bioequivalence
BLQ
below the limit of quantification
BP
blood pressure
CaPS
Clinical Data Interchange Standards Consortium and Pfizer Standards
CDK
cyclin-dependent kinase
CI
confidence interval
Clast
predicted plasma concentration at the last quantifiable time point from the 
log-linear regression analysis
Cmax
maximum plasma concentration
CRF
case report form
CSR
clinical study report
ECG
electrocardiogram
H1
alternative hypothesis
Ho
null hypothesis
HR
heart rate
kel
elimination rate constant estimated from the log-linear regression analysis
LLQ
lower limit of quantification
ms
milliseconds
N/A
not applicable
NC
not calculated
NCA
non-compartmental analysis
ND
not done
NS
no sample
PK
pharmacokinetic(s)
PO
oral(ly)
PR
pulse rate
QRS
Combination of Q-, R- and S- wave on an electrocardiogram representing 
ventricular depolarization
QT
time from the start of the Q- wave to the end of T- wave, which represents 
time taken for ventricular depolarization and repolarization 
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
r2
goodness of fit statistic from the log-linear regression
RR
the time between the start of one QRS complex and the start of the next 
QRS complex
SAP
statistical analysis plan
SD
standard deviation
SoA
schedule of activities
t1/2
terminal plasma elimination half-life
TEAE
treatment emergent adverse event
Tmax
time for Cmax