5. A) To prepare an application for IND submission for Clobazam Tablet in US. B) To prepare IND...

Drug Regulation & Regulatory Authorities

Dept. Of Quality Assurance & Regulatory AffairsL. J. Institute of Pharmacy, Ahmedabad.

EXPERIMENT NO: DATE:

AIM: A) To prepare an application for IND submission for Clobazam Tablet in US. B) To prepare IND checklist in us for Clobazam Tablet.

REFERENCES: 1.) http://en.wikipedia.org/wiki/Clobazam2.) http://www.lundbeck.com/upload/us/files/pdf/Products/Onfi_MG_US_EN.pdf3.) http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=de03bd69-2dca-459c-93b4- 541fd3e9571c4.) http://www.drugs.com/nda/Clobazam_100611.html#c6VaF1QCPxM99P8T.995.)https://www.harvardpilgrim.org/pls/portal/docs/PAGE/PROVIDERS/PHARMACY/3_TIER_PHARMACY/MRFS/ONFI_GLS_41613.PDF

Investigational New Drug Application

1. FDA Forms.2. Table of contents3. Introductory statements & General investigational plan 3.1 Product Information 3.1.1 Product Name 3.1.2 Brand Name 3.1.3 Active & Inactive Ingredient 3.1.4 Pharmacological Information 3.1.4.1 Mechanism Of Action 3.1.5 Structural Formula 3.1.6 Route of Administration 3.1.7 Indication 3.2 Brief summary of previous human experiments 3.3 General investigational plan 3.3.1 Rationale for Clobazam 3.3.2 Indication 3.3.3 Clinical study & no. of patient to be given Clobazam drug for study 3.3.4 Toxicological Data

4. Investigator’s Brochure 4.1 Brief description of Clobazam 4.2 A summary of Pharmacological and toxicological effects of Clobazam 4.3 A summary of pharmacokinetics and biological disposition of Clobazam in animal 4.4 Description of possible risk and side effects to be anticipated on the basis of prior experiment with Clobazam under investigation.5. Protocol 5.1 Study protocol 5.2 Clinical trial investigator information 5.3 Overall clinical trial official and content6. Chemistry Manufacturing and Control data 6.1 Product data 7. Pharmacological and Toxicological data8. Previous human experience



9. Additional information

Content3. Introductory statement and general investigational plan

3.1Product Information:

3.1.1. Product name: Clobazam

3.1.2. Brand name: FRISIUM, URBANOL, ONFI

3.1.3. Active and inactive ingredient: Active ingredient: ClobazamInactive ingredients: corn starch, lactose monohydrate, magnesium stearate, silicon dioxide, and talc.

3.1.4. Pharmacological information: Pharmacological Class of Drug: Antiepileptic drug of the benzodiazepine class

3.1.4.1 Mode of action: Clobazam binds at distinct binding sites associated with the chloride ionopore at the post-synaptic GABA receptor. These GABA receptors are in various locations in the CNS (limbic, reticular formation) and Clobazam increases the duration of time for which the chloride ionopore is open. As a result, hyper polarization and stabilization of the membrane occur as the post-synaptic inhibitory effect of GABA is enhanced.

3.1.5 Structural formula:

Chemical Name: 7-Chloro-1-methyl-5-phenyl-1H-1,5 benzodiazepine-2,4(3H,5H)-dione

Molecular Formula: C16H13O2N2ClMolecular Weight: 300.7

3.1.6 Route of administration: Oral



3.1.7 Indication: Clobazam is approved as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 year and older.

3.2 Brief summary of previous human experiments: Not Applicable.

3.3 General investigational plan

3.3.1 The Rational for ClobazamTo ensure that Clobazam is being used appropriately, as adjunctive treatment agents in patients with Lennox-Gastaut syndrome (LGS). Clobazam belongs to a class of medications called benzodiazepines which have anxiolytic and antiepileptic properties. Outside of the United states, Clobazam has been approved for adjunctive treatment of epilepsy including treatment of the following types of seizure: tonic-clonic, myoclonic, myoclonic-absent, simple-partial, and partial-complex; and short term relief of severe, disabling or distressing anxiety. It is not recommended for use in patients with mild anxiety symptoms.

Additionally, during pivotal phase 3 clinical trials leading to the United States approval of Clobazam in LGS, study subjects were receiving at least one other anticonvulsant medication in addition to ONFI.

3.3.2 Indication: As per 3.1.7

3.3.3 Clinical Studies & No. of patients to be given CLOBAZAM drug for study:

The effectiveness of ONFI for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome was established in two multicenter controlled studies (Study 1 and Study 2). Both studies were similar in terms of disease characteristics and concomitant AED treatments. The most common concomitant AED treatments at baseline included: Valproate, Lamotrigine, Levetiracetam, and Topiramate.

Study 1

Study 1 (N=238) was a randomized, double-blind, placebo-controlled study consisting of a 4-week baseline period followed by a 3-week titration period and 12-week maintenance period. Patients age 2-54 years with a current or prior diagnosis of LGS were stratified into 2 weight groups (12.5 kg to ≤30 kg or >30 kg) and then randomized to placebo or one of three target maintenance doses of ONFI according to Table 5.

Table 5. Study 1 Total Daily Dose

≤30 kg Body Weight >30 kg Body WeightLow Dose 5 mg daily 10 mg dailyMedium Dose 10 mg daily 20 mg dailyHigh Dose 20 mg daily 40 mg daily

Doses above 5 mg/day were administered in two divided doses.



The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to 12-week maintenance period.

The pre-dosing baseline mean weekly drop seizure frequency was 98, 100, 61, and 105 for the placebo, low-, medium-, and high-dose groups, respectively. Figure 1 presents the mean percent reduction in weekly drop seizures from this baseline. All dose groups of ONFI were statistically superior (p≤0.05) to the placebo group. This effect appeared to be dose dependent.

There was no evidence that tolerance to the therapeutic effect of ONFI developed during the 3-month maintenance period.

Study 2

Study 2 (N=68) was a randomized, double-blind comparison study of high- and low-dose ONFI, consisting of a 4-week baseline period followed by a 3-week titration period and 4-week maintenance period. Patients age 2-25 years with a current or prior diagnosis of LGS were stratified by weight, then randomized to either a low or high dose of ONFI, and then entered a 3-week titration period.

The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to the 4-week maintenance period.

A statistically significantly greater reduction in seizure frequency was observed in the high-dose group compared to the low-dose group (median percent reduction of 93% vs 29%; p<0.05).

3.3.4 Toxicological Data

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

The carcinogenic potential of Clobazam has not been adequately assessed.In a limited study in rats, oral administration of Clobazam (4, 20, and 100 mg/kg/day) for 2 years resulted in an increased incidence of thyroid follicular cell adenomas in males at the high dose.

Mutagenesis

Clobazam and the major active metabolite, N-desmethylClobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

There are no adequate studies of the effects of Clobazam on fertility.



4. Investigator’s Brochure

4.1 Brief Introduction of Clobazam Tablet

As per Section 3.1

4.2 A summary of Pharmacological and toxicological effect of Clobazam :-

As per Section 3.3.4

4.3 Summary of pharmacokinetic and biological disposition of Clobazam in animal :-

The metabolism of the 1,5-benzodiazepine Clobazam (CLBZ) was investigated in the rat and in vitro by GC/MS using stable isotope techniques. Coadministration of CLBZ and pentadeuteriophenyl CLBZ to rats facilitated the identification of 4'-hydroxy CLBZ 7,4'-hydroxy N-desmethylClobazam (4'-hydroxy DMC) 5, 3',4'-dihydroxy CLBZ 13, 4'-hydroxy-3'-methoxy CLBZ 14, 3'-hydroxy-4'-methoxy CLBZ 15, and 4'-hydroxy-3'-methoxy DMC 16 in bile as both glucuronide and sulfate conjugates. Metabolites 7, 13, and 14 were present in urine as sulfate conjugates. 4'-Hydroxy CLBZ and 4'-hydroxy-3'-methoxy CLBZ were the major conjugated metabolites in bile and urine, respectively. An unusual in vivo disposition of CLBZ to the O-methyl catechols was discovered. In bile, the para O-methyl catechol 15 constituted 2% of the O-methyl catechols as a glucuronide conjugate, in contrast to constituting 30% (of the O-methyl catechols) as a sulfate. This marks an unprecedented observation of a different catechol O-methyl isomer ratio within the same biological fluid for different conjugate pools. The isotope effect associated with the microsomal N-demethylation of trideuteriomethyl CLBZ was determined. The values of kH/kD were calculated at 5.07 +/- 0.37 (N = 3) and 3.88 +/- 0.23 (N = 4) for control and induced microsomes, respectively.

4.4 A description of possible risk and side effects and to be anticipated in the basis of prior experiment with Clobazam under investigation:-

Blood Disorders: Anemia, eosinophilia, leukopenia, thrombocytopeniaEye Disorders: Diplopia, vision blurredGastrointestinal Disorders: Abdominal distentionInvestigations: Hepatic enzyme increasedMusculoskeletal: Muscle spasmsPsychiatric Disorders: Agitation, anxiety, apathy, confusional state, depression, delirium, Respiratory Disorders: Aspiration, respiratory depressionSkin and Subcutaneous Tissue Disorders: Rash, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), urticaria.



5. Protocol

5.1 Study Protocol

EudraCT Number: 2007-004350-82

Sponsor's Protocol Code Number:

OV-1004

National Competent Authority:

Lithuania - SMCA

Clinical Trial Type: EEA CTA

Trial Status: Completed

Date on which this record was first entered in the

EudraCT database 2008-01-21

Objective of the trial

Main objective of the trial :To determine the long-term safety and effectiveness of open-label Clobazam in the treatment of seizures in subjects with Lennox-Gastaut Syndrome (LGS).

Principal inclusion criteria :

1) The subject or subject’s LAR must sign and date the IRB/IEC approved Informed Consent Form/HIPAA Authorization (if required) prior to study participation.

2) Previous participation in Ovation-sponsored LGS study.3) Subject must weigh greater or equal 12.5 kilograms.4) Male or female subjects must have been between 2 and 60 years of age at the time

of the enrollment in the Phase 3 double-blind study (protocol number OV-1012) or between 2 and 30 years of age at the time of the enrollment in the Phase 2 double-blind study (protocol number OV-1002) study.

5) If female:a. Subject is either not of childbearing potential, defined as premenarchal, postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or if of childbearing potential, must comply with a method of birth control acceptable to the investigator during the study, for at least 4 weeks prior to study entry and for 4 weeks following completion of the study.b. Subject is not breastfeeding.c. Subjects of childbearing potential must have a negative serum pregnancy test at Study Day 1.



6) In the investigator’s opinion, parent or caregiver must be able to keep an accurate seizure diary.

Principal exclusion criteria:

1) Greater than 14 days have elapsed since the subject received his/her last dose of study medication in the previous Ovation-sponsored LGS study.

2) Subject had a serious or severe adverse event in the previous Ovation sponsored LGS study that in the opinion of the investigator was probably or definitely related to Clobazam use and precludes safe use of Clobazam.

3) Subject has had an anoxic episode requiring resuscitation within 6 months of study entry.

4) Subject has a history of an allergic reaction or significant sensitivity to benzodiazepines or to any of the other ingredients in Clobazam tablets.

5) Subject is taking more than 3 concurrent AEDs. NOTE: Vagal Nerve Stimulator (VNS) or ketogenic diet is allowed and will not be counted in the three allowed AEDs.

6) Subject is currently taking long-term systemic steroids (excluding inhaled medication for asthma treatment) or any other daily medication known to exacerbate epilepsy. An exception will be made of prophylactic medication, for example, for idiopathic nephrotic syndrome or asthma.

7) If the subject is taking felbamate, has been taking it for less than 1 year prior to study entry or previous treatment with felbamate resulted in withdrawal due toliver or bone marrow adverse events.

8) Subject has experienced an idiosyncratic reaction to an AED, e.g., carbamazepine with resulting aplastic anemia or agranulocytosis, topiramate with resulting metabolic acidosis, felbamate with resulting aplastic anemia or hepatic failure, or lamotrigine with resulting skin irritation and/or rash.

9) Subject has shown any clinically significant history of hyper-sensitivity to CNS-active medications leading to neurobehavioral aberrations (e.g., increased biting, scratching, kicking, or hitting).

10) Subject has taken or used any investigational drug or device in the 30 days prior to screening, with the exception of Clobazam in an Ovation-sponsored study.

11) Subject has a clinically significant unstable hepatic, hematological, renal,cardiovascular, gastrointestinal, or pulmonary disease or ongoing malignancy.

12) Subject has a diagnosis of sleep apnea.13) Subject has a compromised respiratory function or severe respiratory

insufficiency.14) Subject has a history of severe muscle weakness, including myasthenia gravis.15) Subject has a clinically significant abnormal laboratory value or

electrocardiogram (ECG) abnormality.16) Subject has progressive lesion confirmed by magnetic resonance imaging (MRI)

or computed tomography (CT) scan.17) Subject has a history of drug or alcohol abuse.



18) Subject has a history of poor compliance on past antiepileptic therapy.19) Subject has inadequate supervision by parent or guardian.20) For any reason, the subject is considered by the investigator to be an unsuitable

candidate for the study.

End points

Percent reduction at various time intervals in number of drop seizures (average per week in the week preceding each study visit) compared to the baseline period of the study from which the subject rolled over (previous Ovation sponsored study)

5.2 Clinical trial investigator information: Confidential

5.3 Overall clinical trial officials and contacts: Confidential

6. Chemistry manufacturing and control data

6.1 Product Data

As per Section 3.1

7. Pharmacological & Toxicological Data

As per Section 3.1.4 & 3.3.4

8. Previous human experience

Not applicable

9. Additional information

Not applicable

5. A) To prepare an application for IND submission for Clobazam Tablet in US. B) To prepare IND...

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Transcript of 5. A) To prepare an application for IND submission for Clobazam Tablet in US. B) To prepare IND...