Protocol Training

0568-18
 Study Title
 0568-18 (Dosage strength equivalence study): A multicentric open label, balanced,
randomized, two treatment, two period, two sequence, crossover, steady state, dosage
strength equivalence study of clozapine extended release capsule 25 mg (lowest strength, 25
mg X 8 capsules) once daily (Test drug, Intas pharmaceuticals limited, India) with clozapine
extended release capsule 200 mg (highest strength) once daily (Test drug, Intas
pharmaceuticals limited, India) after multiple dose administration in adult schizophrenic
patients under fasting conditions.

 Regulatory Submission: USFDA

 Study design: Open label, balanced, randomized, two-period, two-
sequence, crossover, multicentric study at steady state in adult schizophrenic
patients stabilized on Clozapine 200 mg per day.
 Number of Patients:
o 0568-18: 82 patients
 Study Population: Adult patient with treatment resistant schizophrenia
stabilized on daily dose of 200 mg clozapine.
 Duration of Study:
 Screening period – 15 days
 Treatment period – 20 days
 Safety follow up period – 15 days
 Objective
 Primary Objective:

0568-18 To assess the dosage strength equivalence of the Sponsor’s formulation clozapine
extended release capsule 25 mg (lowest strength, 25 mg X 8 capsules) once daily
(Test product T1, Intas Pharmaceuticals Ltd., India) with Sponsor’s formulation
clozapine extended release capsule 200 mg (highest strength) once daily (Test product
T2, Intas Pharmaceuticals Ltd., India).

 Secondary Objective:
o To monitor the safety of the patients who are exposed to the
investigational medicinal product.
 Investigational Medicinal Product

0568-18 Test Product – T1

• Clozapine ER 25mg capsule of Intas Pharmaceuticals Limited, India
• Dosage: 200 mg once daily (25 mg X 8 capsules)

Test Product – T2
• Clozapine ER 200mg capsule of Intas Pharmaceuticals Limited, India
• Dosage: 200 mg once daily
 Dosage and Administration

0568-18 Test product T1 (25 mg X 8 capsules, 200 mg once daily) or Test

product T2 (200 mg once daily)

Note:
 The dosing will be continuous for 20 consecutive days.
 There will not be any washout period.
 Fasting criteria
Fasting condition:
 Overnight fast - least 10 hours
 No food for at least 4 hours post-dose.
Fed condition:
 Overnight fast - atleast 10 hours,
 Serving of standardized high fat and high-calorie meal breakfast, to be
consumed within 30 minutes.
 Dosing at 30 minutes (+05 minutes window period) after start of
breakfast
 No food for at least 4 hours post-dose.
Note: Further meals will be at appropriate times.
 Water Restrictions

 No water restriction on Day 01 to Day 9, Day 11 to Day 19.

 Day 10 and Day 20: patients will be adequately hydrated
o 240 ± 02 mL of water after the overnight fast,
o 240 ± 02 mL of water one hour before dosing,
o 240 ± 02 mL of water with the study dose,
o 240 ± 02 mL of water every 2 hours for 6 hours post
dosing with an allowable deviation of ±10 minutes.
 Water will not be allowed for 1 hour before and within 1
hour after dosing.
 Posture Restriction
 Supine or semi-recumbent positions within 15-30 minutes of dosing and for
at least 06 hours after the first dose and for at least 03 hours after subsequent
dosing.
 They will be instructed to rise only with assistance during this period of time
and at the first rising when this period is over.
 All the study activities including sampling on Day 10 and Day 20 will be
carried out bedside for first eight hours.
 Toilet visits will be under supervision and bedpan will be provided if
required till posture restriction after dosing and this will not be considered as
protocol deviation. Thereafter, the patients will be allowed to engage only in
normal activities while avoiding severe physical exertion.
 If the meal timings coincide with the posture restriction period, then patients
will be allowed to have meal either in sitting or semi-recumbent posture.
 Housing
 Patients will be housed in the clinical facility on Day 0 (at least 11 hours
prior to dose 1) till 24 hours after dosing on Day 20 i.e. Day 21.
Note:
 Patient may be allowed to visit home (check-out) in emergency condition
only after permission of principal investigator. Physical examination,
postural hypotension including pulse rate and oral body temperature will be
measured before check out and after check in.
 Patient will be allowed to go out under supervision for protocol defined
investigation and this will not be considered as protocol deviation.
 Investigator will ensure that protocol requirements/restrictions are met at
the time of check-in by asking questions to the patient such as fasting, water
restriction, non-permissible/concomitant medicines, consumption of
alcohol/alcoholic products, smoking and other prohibited items in addition
to concomitant medicines taken by the patient, adverse events, etc.
 Inclusion Criteria
1. Written informed consent for participation in the study by the patient and
Patient’s Legally Acceptable Representative (LAR).
2. Patient has a documented clinical diagnosis of schizophrenia according to
DSM 5 at least six months prior to screening.
3. Patients have a diagnosis of treatment-resistant schizophrenia (Treatment
resistance is the failure to respond to two or more antipsychotic
medications given in therapeutic dose for atleast six weeks).
4. Male and female patients between 18 and 60 years of age (both inclusive).
5. Non-smokers and non-tobacco users in any form.
Note: For this study, non-smoker/non-tobacco user is defined as a person
who has not smoked /consumed tobacco in any form within last six months
prior to screening visit.
 Inclusion Criteria (Conti..)
6. Male patients with weight ≥ 50 kg and female patients with weight ≥ 45 kg.
7. Not having any significant diseases or clinically significant abnormal findings
except schizophrenia during screening-including medical history, physical
examination, laboratory evaluations, 12-lead ECG and X-ray chest (postero-
anterior view) recording, ophthalmic examination etc. which is likely to
adversely affect patient's safety by participating in the study or study
objectives in investigator's opinion.
8. The investigator must ensure that the respective hepatic, renal, haematopoietic,
cardiac and respiratory functions are appropriate to include the patient in the
study.
9. Patients have been on a daily stable dose of 200 mg clozapine formulation for
at least 3 month prior to screening visit.
10. Able to comply with study procedures in the opinion of the investigator.
 Inclusion Criteria (Conti..)
11. In case of Male patients: Either partner or patient must use an effective method of
avoiding pregnancy for at least 4 weeks prior to study drug administration, during
study and up to 30 days after the last dose of study drug. Cessation of birth control
after this point should be discussed with a responsible physician.
12. Sexually active women, unless surgically sterile (at least 6 months prior to study
drug administration) or postmenopausal for at least 12 consecutive months, must
use an effective method of avoiding pregnancy (including oral, transdermal, or
implanted contraceptives [any hormonal method in conjunction with a secondary
method], intrauterine device, female condom with spermicide, diaphragm with
spermicide, absolute sexual abstinence, use of condom with spermicide by sexual
partner or sterile [at least 6 months prior to Study drug administration] sexual
partner) for at least 4 weeks prior to study drug administration, during study and
up to 30 days after the last dose of study drug. Cessation of birth control after this
point should be discussed with a responsible physician.
 Exclusion Criteria
1. Patient with known hypersensitivity/ intolerance to clozapine or any other
component of the drug.
2. Clinically symptomatic orthostatic hypotension.
Note: Orthostatic hypotension is defined as a drop in systolic blood pressure of 20
mm Hg or more and/or a drop in diastolic blood pressure of 10 mm Hg or more on
standing.
3. Concurrent use of antihypertensive medication or any medication that might pre-
dispose to orthostatic hypotension.
4. Supine blood pressure less than 110/70 mm Hg or pulse rate less than 60 or more
than 100 beat per minute at screening and Day 0.
5. Concurrent primary psychiatric or neurological diagnosis (except schizophrenia),
including organic mental disorder, severe tardive dyskinesia, or idiopathic
Parkinson’s disease.
6. An absolute neutrophil count <1500/µL performed at the screening and a day prior
to randomization.
 Exclusion Criteria (Conti..)
7. A history of granulocytopenia, agranulocytosis or myeloproliferative disorders
(drug-induced or idiopathic).
8. A history of epilepsy or risk for seizures, paralytic ileus, or multiple syncopal
episodes.
9. A medical or surgical condition that might interfere with the absorption,
metabolism, or excretion of clozapine.
10. Known case of poor metabolizer individuals with reduced activity of cytochrome
P450 enzymes particularly, 1A2, 2D6 and 3A4.
11. Ingestion of any restricted medication at any time within 07 days before the first
study drug administration.
12. Positive tests for drug or alcohol abuse at screening and baseline.
13. A history of alcohol or drug dependence by Diagnostic and Statistical Manual of
Mental Disorders V (DSM 5) criteria during the 6-month period immediately prior
to study entry.
 Exclusion Criteria (Conti..)
14. Donation of blood (1 unit or 350 ml) within 90 days prior to receiving the first
dose of study medication or during the study.
Note: In case the blood loss is less than or equal to 200 ml; Patient may be
dosed 60 days after blood loss.
15. Receipt of an investigational medicinal product or participation in a drug research
study within 90 days prior to receiving the first dose of study medication or during
the study.
Note: Elimination half-life of the study drug should be taken in to
consideration for inclusion of the patient in the study.
16. A known case of or positive test for HIV infection or hepatitis B or HCV.
17. Known history of hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose galactose malabsorption.
18. Psychosis judged to be the direct physiological effect of an abused medication or
substance.
 Exclusion Criteria (Conti..)
19. Hospitalisation for an exacerbation of schizophrenia within two months prior to
screening and during the screening period.
20. Patients who, in the opinion of the investigator, pose an imminent risk of suicide or
a danger to self or others.
21. Patients with the following cardiac conditions are excluded:
 Recent myocardial infarction (<12 months).
 QTc prolongation (screening electrocardiogram with QTc>450 msec).
 History of QTc prolongation or using concomitant medications which prolong
QTc interval.
 First-degree heart block with PR interval > 0.22 seconds.
 Sustained cardiac arrhythmia or history of sustained cardiac arrhythmia.
 Uncompensated congestive heart failure, myocarditis, cardiomyopathy.
 Complete left bundle branch block.
 Exclusion Criteria (Conti..)
22. Presence of narrow angle glaucoma assessed by tonometry.
23. Patient with hypokalemia and / or hypomagnesemia.
24. Patients with uncontrolled diabetes mellitus or fasting blood glucose ≥ 126 mg/dl
at screening visit.
25. Patient with hyperprolactinemia at screening visit which as judged by Investigator
could lead to safety risk to the patient upon participation in the trial or could
interfere with the conduct of the trial.
26. Dementia related psychosis.
27. Concurrent use of other drugs known to suppress bone marrow function.
28. Pregnant or lactating females.
29. A history of risk for seizures.
30. Compliance with outpatient medication schedule not expected.
31. Expected changes in concomitant medications during the period of study.
 Withdrawal Criteria
The investigator may withdraw a patient from the study for any of the
following:
1. The patient suffers from significant intercurrent illness or undergoes
surgery during the course of the study or the patient has any significant
symptoms or signs during the course of the study.
2. An absolute neutrophil count <1000/ µL at any time during the course of
study post randomization.
3. Patient whose QTc interval exceeds 500 msec.
4. Patients developing clozapine related eosinophilia (700/µL) that is
associated with myocarditis, pancreatitis, hepatitis, colitis or nephritis.
5. Any patient requiring dose modification due to any reason during the
course of study post randomization.
 Withdrawal Criteria (Conti..)
6. Any patient found to have entered the study in violation of this protocol. This
would include pre-study directions regarding drug use, fasting or if the patient is
uncooperative during the study.
7. If it is felt in Investigator’s opinion that it is not in the patient’s best interest to
continue in the study.
8. Any patient who wishes to withdraw his/her consent.
9. Any Patient who requires the use of an unacceptable concomitant medicines
(including herbal remedies).
10. Any other justifiable reason, which should be adequately documented.

 In case of emesis any time during the dosing interval i.e. 24 hours from the time of
IMP administration.
 Sampling Schedule

 Total - 54 blood samples during entire study.

Pre-dose blood sample (Day 07 to Day 10 and Day 17 to Day 20)

Post-dose blood sample (Day 10 and Day 20):

 Post dose blood samples each of 04 mL will be withdrawn at 0.500, 1.000, 1.500, 2.000,
2.500, 3.000, 3.500, 4.000, 4.500, 5.000, 5.500, 6.000, 6.500, 7.000, 7.500, 8.000, 9.000,
10.000, 12.000, 14.000, 16.000, 20.000 and 24.000 hours of dosing.
 Sampling Schedule (Conti..)
Note:
 Blood sample collection (PK samples) will be collected first if other activities are
coinciding.
 All post-dose PK samples will be collected within ±2 minutes of the scheduled
collection time except for 24 hours post dose sample on day 10 and day 20.
 At 24 hours post dose sample on day 10 and day 20, PK sampling time and dosing
time coincides; hence, sample will be collected within -5 minutes of scheduled
collection time.
 The actual time of collection of each blood sample will be recorded immediately
after blood collection and same will be captured along with actual time of dosing.
 Delay beyond ±2 minutes will be considered as deviations.
 Total Blood Loss
 Not exceeding 277 + 10 mL for all the patients for entire study as follows:

Procedure Blood loss

Blood volume for the PK samples for both the periods: : 216 mL
46 post-dose samples and 08 pre-dose samples of 04 mL each
Discarded blood with normal saline for all periods (46 x 0.5 mL) : 23 mL
Safety assessment (Screening) : 10 mL
Safety assessment (ANC on Day 0 and Day 10 (post-dosing)) : 04 mL
Safety assessment [ANC on Day 05 (post- dosing), Day 15 (post-dosing)] : 04 mL
Safety assessment (Before dosing of Day 11) : 08 mL
Safety assessment (End study, Day 21) : 08 mL
Safety assessment (ANC on every week for 15 days after last study drug : 04 mL
administration 2 mL X 2)
Total Blood Loss for each Patient for entire study duration : 277 mL
Note: In addition to above up to additional of 10.0 mL blood sample will be collected if required, for
hemolysed sample or clotted sample or sample loss or any other reason.
Thank You