Protocol Number : LRP/VGFDPI/2021/004

Sponsor-Lupin Limited, India

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Agenda

 Introduction
 Study overview and design
 Rationale
 Objectives and study population
 Point Ordinal Scale by WHO
 Eligibility criteria (inclusion and exclusion criteria)
 Withdrawal criteria
 Flow chart of study design
 Study drug description
 Concomitant and Permitted Therapy
 Essential document list

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 Introduction
• Chronic obstructive pulmonary disease (COPD) is a progressive disease that leads to airflow limitation and persistent
respiratory symptoms, is characterized by exacerbations and commonly presents with multiple comorbidities.
• The estimated prevalence of COPD in India is between 6.5-7.7%.

• The pathogenesis of COPD is strongly linked to the effects of cigarette smoke on the lungs.

• INVESTIGATIONAL AGENT- Lupin’s Glycopyrronium 50 µg + Vilanterol 25 µg + Fluticasone 100 µg dry powder

inhaler (DPI) for once-a-day inhalation
• REFERENCEE AGENT-Glycopyrronium 12.5 µg + Formoterol 12 µg + Fluticasone 250 µg DPI (marketed by
Glenmark Pharmaceuticals Ltd) for twice a day inhalation.

• It is a pre-metered capsule-type unit-dose dry power inhaler (DPI) delivering a blend of active ingredient (Vilanterol,
Fluticasone Furoate & Glycopyrronium), lactose monohydrate and magnesium stearate, contained in a hydroxypropyl
methylcellulose (HPMC) capsule.

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 Study Overview and design

Study Title: A Multi-center, Randomized, Open-label, Comparative, Parallel Group study to assess the
efficacy and safety of a fixed dose combination of Lupin’s Glycopyrronium + Vilanterol + Fluticasone dry
powder inhaler versus fixed dose combination of Glycopyrronium + Formoterol + Fluticasone dry powder
inhaler in patients with Chronic Obstructive Pulmonary Disease.

Phase of study: III

Indication Under Investigation: Chronic obstructive pulmonary disease (COPD)
Design: This is a multi-center, randomized, open-label, comparative, parallel group study.
Number of Patients : 278 patients (139 patients in each arm)

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Study Overview and Design
Treatment Groups:
Arm 1: Lupin’s Glycopyrronium + Vilanterol+ Fluticasone dry powder inhaler
Arm 2: Glycopyrronium + Formoterol +Fluticasone dry powder inhaler (marketed by Glenmark
Pharmaceuticals Ltd.)

Study duration
Approximately 14 weeks (Screening up to 10 days [including run-in period of at least 7 days] and Treatment
period: 12 weeks)

The study consists of a screening period of up to 10 days which is inclusive of run-inperiod of at least 7 days
and randomized treatment period of 12 weeks.

The total duration of the study is 14 weeks for Individual Patient.

During the run-in period, subjects will continue the use of their existing COPD medications and in addition will
be provided with short acting salbutamol to be used on an as-needed basis (rescue medication) throughout the
study. Subjects who successfully complete the run-in period and fulfill all inclusion/exclusion criteria based on
screening procedures will be randomized to receive study medication
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 Flowchart

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Study Visits

Activity / Observation Visit 1   Visit 2 Visit 3 Visit 4 Visit 5

Screening (Basel EOS/Early
ine/ termination
Randomization
Visit)

Study Day Day -10 to Week 0 (Day 1) Week 4 (±3 Week 8 (±5 Week 12
Day 0 days) days) (±5days)
Informed Consent X - - - -
Demography X - - - -
Medical & Surgical X - - - -

Run-In period atleast 7 days starting from day of signing

History
Inclusion and Exclusion X X - - -
criteria
Vital Signs X X X X X
Physical Examination X X X X X
Prior Medication history X - - - -
Chest X-raya X        
informed consent

Rapid antigen test for X        

SARS-COV2b
Haematology,
biochemistry, Urinalysis
12-lead ECG
Serum Pregnancy Test
for female patients
Urine Pregnancy Test
X - - - X
X - X X X
X - - -  
- X - - X
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 Study Visits
for female patients            
Rapid antigen test for X        
SARS-COV2b
Dispensing of subject X X - - -
Diary
Dispensing of rescue X X X X -
medicationc
Randomization - X - - -
Training on use of - X      
inhaler device
Dispensing of Investigational - X X X -
Productd
IP administration   X X X X
Spirometry e
X X X X X
mMRC assessment X X X X X
Retrieval of Subject - X X X X
diary
Adverse Event X X X X X
assessment
COPD X X X X X
exacerbation
assessment

Concomitant - X X X X
Medications

Retrieval of used and -   - X X X

unused IPs
Retrieval of rescue -   - - - X 8
medication
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Study Details
Rationale
Treatment of COPD is typically initiated with a single bronchodilator (long- acting muscarinic antagonist
[LAMA] or long-acting β2-agonist [LABA]), with the addition of a second bronchodilator and/or an
inhaled corticosteroid (ICS), if necessary, to control symptoms and decrease the risk of exacerbations.
A combination of bronchodilators such as a LABA and a LAMA that target different bronchodilation
pathways has been shown to enhance bronchodilation in symptomatic patients. A single inhaler triple
therapy of LABA/LAMA/ICS not only improves the lung function and reduces the frequency of
exacerbation in moderate to severe COPD cases, but it also helps to reduced burden of polypharmacy
thereby enhancing patient compliance and quality of life. Multiple triple therapy fixed dose combinations
containing LABA+LAMA+ICS are approved globally as well as in India.

Study Population

Male or female patients, aged ≥18 to ≤ 75 years at screening with a diagnosis of COPD (as defined by the
GOLD Guidelines, 2021) .
Post-bronchodilator FEV1 ≥30% and <80% of the predicted normal value and post-bronchodilator
FEV1/FVC (forced vital capacity) ratio <0.70.

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Study Objectives

Study Objective:

Primary objective: To evaluate efficacy of FDC dry powder inhaler (DPI) of Lupin’s Glycopyrronium +
Vilanterol + Fluticasone, in comparison to approved DPI containing Glycopyrronium + Formoterol +
Fluticasone in patients with moderate to severe COPD.
•Secondary objective:
• To evaluate the safety and tolerability of FDC dry powder inhaler (DPI) of Lupin’s Glycopyrronium
+Vilanterol+ Fluticasone in comparison to approved DPI containing Glycopyrronium + Formoterol
+Fluticasone in patients with moderate to severe COPD.

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Study Endpoints

Primary Endpoint:

• Change from baseline in trough FEV1 at week 12

Secondary Endpoints

• Change from baseline in trough FEV1 at week 4 and week 8

• Change from baseline in 2 h post-dose FEV1 at week 12
• Proportion of patients requiring use of rescue medication over treatment period
• Proportion of patients with COPD exacerbations during the treatment period of 12 weeks
• Change from baseline in mMRC score at week 4, week 8 and week 12

Safety Endpoint:

• Incidence of TEAEs (based on laboratory parameters, physical examination, vitals, ECG, etc.)

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MRC Grade Score

MRC Grade Symptoms

Grade 1 Not troubled by breathlessness except on strenuous exercise.
Grade 2 Short of breath when hurrying or walking up a slight hill.
Grade 3 Walks slower than contemporaries on level ground because of breathlessness, or must
stop for breath when walking at own pace.
Grade 4 Stops for breath after walking about 100 meters or after a few minutes on level ground.
Grade 5 Too breathless to leave the house or breathless when dressing or undressing

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Inclusion Criteria

Subjects meeting all of the following criteria will be recruited for the trial :

1. Male or female patients, aged ≥18 to ≤ 75 years at screening .

2. Patients with a diagnosis of COPD (as defined by the GOLD Guidelines, 2021) .
3. Post-bronchodilator FEV1 ≥30% and < 80% of the predicted normal value and post-bronchodilator
FEV1/FVC (forced vital capacity) ratio <0.70.
4. A modified Medical Research Council dyspnoea scale (mMRC) grade 2 or greater.
5. History of exacerbations (≥2 moderate or ≥1 severe exacerbation) of COPD within 12 months before
screening

6. Subjects on inhaled corticosteroid (ICS) with or without a long-acting β2 agonist (LABA) (as a free or fixed
combination), or ICS with a long- acting muscarinic antagonist (LAMA), or LABA with LAMA (as a free
or fixed combination), or LAMA monotherapy as maintenance treatment for at least 1 month before
screening.

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Inclusion Criteria

7. Current or previous cigarette/beedi smokers with a history of cigarette/beedi smoking of at least 10

pack/years. (Previous smokers are defined as those who have stopped smoking for at least 6 months prior to
Screening Visit.)
8. Willingness to give their written informed consent to participate in the study and willing to comply with
study requirements and procedures.
9.Female subjects with negative pregnancy test and agree to use adequate forms of nonhormonal
contraception during the study (i.e. women of child-bearing potential who use a highly effective method of
birth control, such as condom and spermicide, diaphragm or cervical cap and spermicide, condom and
diaphragm or cervical cap, nonhormonal IUD), or females of nonchild bearing potential i.e. surgically
sterile (history of hysterectomy or bilateral tubal ligation or bilateral oophorectomy; partial hysterectomy
is not sufficient or vasectomized partner) or postmenopausal (12 months of spontaneous amenorrhea), or
who agree to remain abstinent.
10. Male subjects who are willing to either remain abstinent or use a highly effective method of birth
control as described above.
11. Ability to use dry powder inhaler independently and correctly in view of the investigator.

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 Exclusion Criteria
Subjects who will not meet any of the following criteria will be included in the trial:
1. Patient unable to perform study procedures or to give informed consent
2. Patients who are currently receiving dual drug treatment with LABA+LAMA+ICS
3.Known respiratory disorders other than COPD including, but not limited to the following: tuberculosis, alpha-1
antitrypsin deficiency, cystic fibrosis, asthma, active bronchiectasis, sarcoidosis, lung fibrosis, pulmonary
hypertension, pulmonary edema, or interstitial lung disease
4. Evidence or history of other clinically significant cardiovascular disease or abnormality (such as, but not
limited to, congestive heart failure, uncontrolled hypertension, uncontrolled coronary artery disease, myocardial
infarction, arrhythmia, long QT syndrome, atrial fibrillation), renal, neurological, endocrine, immunological,
psychiatric, hepatic, or hematological disease or abnormality which, in the opinion of the investigator, are
clinically significant and would put the patient at risk through study participation, or would affect the study
analyses if the disease exacerbates during the study
5. Significant abnormality that suggests chest disease other than COPD, on chest X-ray or computed tomography
(CT) scan taken within six months before screening. If there is no chest X-ray/CT scan is taken within six
months prior to screening, a chest X-ray will be performed during screening to rule out any other significant
abnormality.
6. History of paradoxical bronchospasm, narrow-angle glaucoma, prostatic hyperplasia, bladder neck obstruction,
or severe renal impairment or urinary retention or any other condition, which, in the opinion of the investigator,
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would contraindicate the use of an anticholinergic or long acting beta-agonist agent.
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Exclusion Criteria

7. History of allergy or hypersensitivity to any of the ingredients of study drugs or components of the delivery
system.
8. Suspected or confirmed SARS-COV2 infection at screening (prior to randomization the subjects will be
tested for COVID 19 through rapid antigen test).
9. Hospitalization for COPD exacerbation or pneumonia within three months prior to screening. Any subject
who experiences pneumonia and/or moderate or severe COPD exacerbation during the run-in period will be
excluded.
10.Use of oral/parenteral corticosteroids or antibiotics for COPD exacerbation within six weeks prior to
screening.
11. Clinically significant abnormal electrocardiogram (ECG) finding at screening.
12. Lung volume reduction surgery within 12 months prior to the initiation of the study.
13. Requirement of long term (> 12 hours daily) oxygen therapy.

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Exclusion Criteria :
14. Unable to stop the following medications at the defined times prior to screening spirometry:

Medication Required washout period prior to screening spirometry

Ipratropium or ipratropium/salbutamol combination product 8 hours
Inhaled short acting β-agonists 6 hours
Oral β 2-agonists 48 hours
Long acting β-agonists (salmeterol and formoterol) or ICS/LABA 48 hours
combination products
Xanthines 48 hours
Cromolyn and nedocromil inhalers 24 hours
Zafirlukast, montelukast, zileuton 48 hours
Long acting anticholinergics (Tiotropium etc.) 48 hours
Oral or parenteral corticosteroids 6 weeks
Any other investigational medication 30 days or 5 half-lives of the investigational drug (whichever is
longer)
Depot corticosteroids 3 months
Inhaled corticosteroids (ICS) Washout not required

15. Currently enrolled in another interventional clinical study or have used any IPs, study drug,
or device within 30 days or 5 times the half-life, whichever was longer preceding informed
consent or scheduled to participate in another clinical study involving an IP.
Additional exclusion criteria for Run-In period:
COPD exacerbation requiring treatment with antibiotics, systemic corticosteroids (oral or
intravenous), and/or a hospitalization during screening and run-in period

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 Prohibited Medication
The following medications are not permitted during the total study period, starting from screening visit.
(Unless they are used for treatment of COPD exacerbation) (Subjects who take any of these medications
during the randomized treatment period will be carefully evaluated by the investigator for Early
Withdrawal based on the potential impact on efficacy or safety evaluations and in the best interest of the
subject.)
1. Other Inhaled long acting β2-agonists.
2. Inhaled fixed combination of corticosteroids and long-acting β2-agonists (e.g., salmeterol plus
fluticasone or formoterol plus budesonide).
3. Inhaled short acting β2-agonists (other than study “rescue” medication).
4. Inhaled fixed combinations of a short-acting β2-agonist (SABA) and a short-acting anticholinergic
medication (SAMA).
5. Inhaled short-acting anticholinergics
6. Inhaled long-acting anticholinergics
7. Oral/IV/IM corticosteroids
8. Nebulized bronchodilators or corticosteroids.
9. Inhaled corticosteroids other than study background ICS.
10. Non-cardio selective β-blockers
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Prohibited Medication

11. PDE4 inhibitors (e.g., roflumilast).

12. Leukotriene modifiers (e.g. Zafirlukast, Montelukast, Zileuton)
13. Xanthine derivatives (e.g., theophylline).
14. Any drug with known or possible risk of Torsade’s de Pointes (TdP) or QT interval prolongation (e.g.,
quinidine, procainamide, amiodarone).

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 Withdrawn criteria

• Any medical condition that the Investigator determines may jeopardize the patient's safety if he or she continues to
receive study treatment .
• Withdrawal of consent .
• Pregnancy (report on Pregnancy Notification Worksheet).
• Use of Prohibited Medications that interferes with the investigational product or study assessments
• Repeated non-compliance to protocol .
• Any physical examination finding, change in vital signs or any AE leading to drug discontinuation or any other
laboratory abnormality which possess an unacceptable risk to patient’s health .
• Disease progression leading to requirement of other therapies

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 Study Discontinuation

The Sponsor has the right to terminate this study at any time. Reasons for terminating the study may include, but are not
limited to, the following:

• The incidence or severity of AEs in this or other studies indicates a potential health hazard to patients .
• Patient enrolment is unsatisfactory
• Administrative decision by the Sponsor

The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study.

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 Study Drug Description

• Investigational Agent- Lupin’s Glycopyrronium 50 µg + Vilanterol 25 µg + Fluticasone

100 µg dry powder inhaler (DPI) for once-a-day inhalation.
Storage condition: Store below 25°C. Protect from moisture

• Reference Agent- Glycopyrronium 12.5 µg + Formoterol 12 µg + Fluticasone 250 µg DPI

(marketed by Glenmark Pharmaceuticals Ltd) for twice a day inhalation.
Storage condition: Store below 25°C. Protect from moisture

Treatment Regimen with Administration of Study Drug

Trial medication will be dispensed to the patient by the investigator/pharmacist. Study

medication administration at clinic visits:
• At each clinic visit, oral inhalation of the study medication inhaler will be self-administered
by the patient under the direct supervision of the investigating physician or site staff. The
investigator or qualified study personnel will observe the inhalation procedure.
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 Study Drug Administration at home

• Patients should be encouraged to take their study medication at approximately the same time in the morning
(morning dose window until noon). If a patient misses the daily dose he/she should take the next dose the day after.
The patient will be asked to record any missed dose of study

• Throughout the course of the study treatment period, the correct usage of their inhalation medications should be
regularly re-instructed (ideally at each clinic visit) based on the package insert.

• In the event that a patient may need additional extra inhalers due to rescheduled visits, inhaler loss or malfunction,
these will be supplied on an ‘on demand’ basis. Site personnel will enter all medication numbers dispensed to each
patient and maintain accountability of used and unused medications.

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Concomitant Therapy

Permitted concomitant Medication:

• 1. Short-acting β2-agonist (albuterol/salbutamol) as rescue medication. A minimum period of 4 hours

should elapse between the use of rescue medication and the spirometric measurements.
• 2. Mucolytics (e.g. N-acetyl cystein) if taken prior to study entry and maintained constant during the
study period.
• 3. Intranasal corticosteroids and oral, intranasal, or ocular antihistamines at approved doses for the
treatment of allergy symptoms will be allowed during the study period.
• 4. Cardioselective β1-blockers which are ongoing prior to screening and to be maintained at stable dose
during the study.

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 Thank You!

JSS Medical Research Asia Pacific Private Limited

Tower 2, 1st Floor, South Wing, L&T Business Park, Plot no 12/4 , Sector 27 D, Sarai Khwaja
Metro Station, Mathura Road, Faridabad-121003, www.jssresearch.com
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