ASSESSMENT OF THE SAFETY AND EFFICACY OF GRC-3886 IN THE TREATMENT OF MILD TO MODERATE PERSISTENT ASTHMA PATIENTS

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ASSESSMENT OF THE SAFETY AND EFFICACY OF GRC-3886 IN

THE TREATMENT OF MILD TO MODERATE PERSISTENT

ASTHMA PATIENTS

*Mathew George1*, Lincy Joseph2, Vishal Thakkar3, Jisha Annie4

1

Department of Pharmacology, Pushpagiri College of Pharmacy, Thiruvalla, 689107, Kerala.

2

Department of Pharmaceutical Chemistry, Pushpagiri College of Pharmacy, Thiruvalla, 689107, Kerala.

3

Department of Pharmaceutical Management and Regulatory Affairs, School of Pharmaceutical Sciences, Jaipur National University, Jaipur, Rajasthan.

4

Department of Pharmacy Practice, Pushpagiri College of Pharmacy, Thiruvalla, 689107, Kerala.

ABSTRACT

Oral Type 4 phosphodiesterase inhibitors (e.g. roflumilast) have provided evidence of clinical efficacy in both asthma and chronic obstructive pulmonary disease (COPD). The objectives were to evaluate the efficacy, safety and tolerability of oglemilast at 3 dose levelscompared with placebo for the treatment of mild to moderate persistent asthma, to investigate the pharmacokinetics of oglemilast and its N-oxide metabolite, to investigate the effects of oglemilast on pharmacodynamics parameters in sputum and blood. This is a randomized, double-blind, placebo controlled, parallel group phase II study to evaluate the efficacy of 3 doses (0.2, 0.4, 0.8 mg) of drug-x administered for 12 weeks once daily. A total of 30 patients of mild to moderate persistent asthma were screened. From the 30 patients, total 27 patients are eligible for randomization and they get the Drug-x as well as placebo. In the study, the spirometry and symptom score which are recorded by the patient in their dairy for evaluation of result of the study were taken. Patients brought for the study medication their paper diary to every study visit. Safety status assessed by clinical laboratory tests, vital signs, physical examination (including electrocardiogram [ECG]), monitoring of asthma symptoms and adverse events. It was seen that patients who received the Drug-x shows marked

Volume 5, Issue 6, 2128-2140 Research Article ISSN 2278 – 4357

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improvement in spirometry parameters from visit V1 to visit Vend. Drug-x has significant safety profile and it can be used for management of asthma.

KEYWORDS: Type 4 phosphodiesterase inhibitors, Safety, Efficacy, Spirometry, Asthma.

INTRODUCTION

Drug treatment of asthma has focused on anti-inflammatory therapy (e.g. inhaled corticosteroids and leukotriene antagonists) in all but the mildest, intermittent cases. Although safe, leukotriene antagonists have limited efficacy, with only small increases in pulmonary function demonstrated in clinical trials1,2,3.

In asthma, there remains a need for the development of novel anti-inflammatory therapies that are at least equally and possess a superior safety profile in comparison to corticosteroids. Type 4 phosphodiesterase (PDE4) is an isoenzyme that is expressed in the inflammatory cells and in several other airway cells involved in the pathogenesis of asthma. Oral PDE4 inhibitors (e.g. roflumilast) have provided evidence of clinical efficacy in both asthma and chronic obstructive pulmonary disease (COPD) in Phase II and III clinical studies attributed to their beneficial anti-inflammatory effects4,5,6. However, most PDE4 therapies may cause nausea, vomiting, abdominal pain and diarrhoea, as dose-limiting side effects. Thus, further efforts are needed to develop PDE4 inhibitors with an improved therapeutic margin.

Oglemilast is a potent (inhibitory concentration [IC] 50= 1nM) and specific inhibitor of PDE4, with almost equipotent inhibition of PDE4 A, B, D subtypes and slightly less effect on PDE4 C isoform. The potency of oglemilast in invitro assays is similar to that of roflumilast, and oglemilast is about50 times more potent than cilomilast.

AIM

A phase II, 12- Week Randomized, Double-Blind, Parallel Group, Placebo-Controlled Dose Range Finding Study to Evaluate the Efficacy of Drug-x in the Treatment of Stable Mild to Moderate Persistent Asthma.

OBJECTIVES

1. To evaluate the efficacy of oglemilast at 3 dose levels compared with placebo for the treatment of mild to moderate persistent asthma.

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3. To investigate the pharmacokinetics of oglemilast and its N-oxide metabolite (in around 28 patients selected sites with appropriate facilities).

4. To investigate the effects of oglemilast on pharmacodynamics parameters in sputum and blood.

MATERIALS AND METHODS

This is a randomized, double-blind, placebo controlled, parallel group phase II study to evaluate the efficacy of 3 doses (0.2, 0.4, 0.8 mg) of drug-x administered for 12 weeks once daily.The study consists of the Run in period (2 weeks): visits V1 and the Randomization period (12 weeks): visits V2 (Randomization), V3, V4, V5, V6, V7, V8, and follow up visit.Patients with Asthma who meet inclusion criteria entered the single-blind run in period. All Asthma medication is not allowed during run in and randomization period and must be stopped at V1. But rescue medication (salbutamol) should be used throughout the entire study on an “as-needed” basis.

During run in period, patients received one placebo tablet once daily in the morning after breakfast. On completion of the run in period, patients re-evaluated and those who meet randomization criteria should be randomized in a 1:1:1:1 ratio to receive Drug-x 0.2, 0.4, 0.8 mg or placebo.

During the randomization period, patients will record their use of rescue medication and their asthma symptoms in a diary as before. After 1, 3, 5, 7, 9, 12, weeks (V3, V4, V5, V6, V7, and V8, respectively) further lung function tests and safety monitoring as well as health economic assessments performed at site visits. Visits are to be scheduled such that lung function tests will be performed within ± 2 hours of the time at which the lung function test was done at visit V2. Drug-x versus placebo. All other data evaluated as secondary parameters. Safety status assessed by clinical laboratory tests, vital signs, physical examination (including electrocardiogram [ECG]), monitoring of asthma symptoms and adverse events.

Risk/Benefit Assessment

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side effects. Additionally, Drug-x offers the possibility of once daily oral dosing. The benefit to risk ratio for Drug-x in the anti-inflammatory treatment of asthma is clearly favorable. Sample size

A total of 25 patients should be randomized (i.e. 30 per treatment arm). The study will be conducted in approximately 25 sites in India. Following the provision of written informed consent patients will be screened according to the eligibility criteria. The patient will be considered to have entered the study once informed consent is provided. At this point, a patient identification code (patient number) will be assigned, which (together with his/her initials) will ensure unambiguous identification throughout the study. Patients who withdraw (for any reason) without successfully completing all screening evaluations (i.e. at screening and prior to randomization) will be considered to be screening failures. Any available data for patients providing consent including screening failures must be recorded into the CRF. The screening section and patient summary (study exit) page of the CRF will be completed for screening failures.

Inclusion Criteria

Patients will be eligible for enrolment into the study if all of the following criteria are met at the screening visit (visit 1) which includes Male and female patients aged 18-65 years, Documented clinical history of reversible obstructive airway disease of at least 6 months duration at the time of the visit 1 for patients already receiving asthma controller treatment, No change in the patient‟s asthma treatment within 4 weeks prior to visit 1 for patients who are on anti-asthma medications, No exacerbations of asthma within 4 week prior to visit 1, No upper or lower airway infections within 4 weeks prior to visit 1 and FEV1 between 60% and 85% of the predicted value for their age, height and gender at screening.

Exclusion Criteria

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investigator considers detrimental to the patients participation in the study or that may prevent the successful completion of the study, any clinically significant laboratory abnormality, Pregnant or lactating women, Currently immunocompromised or treatment with an immunosuppressant agent.

Randomization Criteria

In addition, the following randomization criteria must be confirmed at the randomization visit (visit 2):

 At least 80% compliance during the single-blind placebo run-in period.

 FEV1 between 60% and 85% of the predicted value for their age, height and gender.  Without asthma exacerbation during the run-in period.

 Reversibility: patients are required to demonstrate a ≥ 12% increase in FEV1 (with an absolute improvement in FEV1 of at least 200ml) ≥ 10 min and up to 15 minutes after inhalation of 400 µg salbutamol via a spacer.

Note: Reversibility should be determined at the time of randomization. At the investigators discretion, if a patient fails to meet the ≥ 12% threshold, the reversibility tests may be repeated to a maximum of four measurements. However, the study visit window should be respected.

 Use of salbutamol for symptom relief on > 2 occasions ( defined as ≥ 1 puff administered during the night or a total of ≥ 2 puffs daily [24 hours]), on at least 4 out of the last 7 days of the run-in (based on the patient dairy, with the day before the randomization visit being day 7).

General Study Conduct

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Screening of patients- Run in Period

Prior to any study specific investigation the patient should be informed verbally and in writing about the purposes (aims, methods, anticipated benefits and potential hazards) of the trial, and written informed consent to study participation from the patient should be obtained. a) Screening, Visit 1 (Week – 2, day – 14 ± 2)

Patients, for whom written informed consent had been obtained, undergo the following assessments Baseline eligibility – check of inclusion, exclusion criteria :Demographic data (age, sex, race, body weight and height), Qualifying FEV1 value, Medical history and the documenting of any concurrent diseases, Physical examination, eye examination, ECG, vital signs, and safety laboratory tests, Serology (HIV and hepatitis B and C), Prior and concomitant medications, Adverse events will be elicited by the open question “Have you experienced any problems since signing the informed consent form?”, Urine human chorionic gonadotropin pregnancy test any female patients of child-bearing potential at screening (kits will be provided to site).

Following the screening visit (visit 1), eligible patients will enter a 2- week single- blind run-in period for wash out; thus all asthma medications (except for run-inhaled salbutamol) will be discontinued at visit 1 and the patient will start treatment with the placebo. Patients will be dispensed with the single blind study medication for 2 week run in period and inhaled salbutamol as a rescue/reliever medication. The patient‟s peak expiratory flow (PEF), asthma symptoms, salbutamol use, and compliance will be recorded in the dairy. Patients will be requested to bring the dairy to the next visit.

Patients will be reminded to only use salbutamol as their reliever medication. The study co-ordinator will schedule the date and time for the next visit and remind patients regarding the restrictions.

b) Study Medication at Run in period

Single blind medication for the period V1-V2 should be handed over to the patient at V1. The medication kit should contain single blind medication for 2 weeks. Additionally, the patient should receive salbutamol MDI.The patients should be asked to return all excess medication, including rescue medication and empty blisters and cartons.

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clinical study, and the name and address of the respective investigator. The patient should be scheduled for return visits to the investigational site after visit V1 and should be advised not to take their study medication in the morning of the next study visit day.

Treatment Study Medication

At visits V2 to V8, the respective study medication should be handed over to the patient. The tear-off part of the study medication label has to be transferred to the Drug Dispensing section of the CRF by the investigator, pharmacist, or authorized personnel. Additionally, the patient should receive further rescue medication, if needed. The patients should be asked to return all excess medication, including rescue medication and empty blisters and cartons at each visit.

Study Termination

For each randomized and also non-randomized patient terminating the study (either as scheduled or prematurely), the termination record of the CRF has to be completed. For patients terminating prematurely, the reason for the premature termination has to be documented. The confirmation of the clinical investigator, that the patient has been treated under his/her supervision and in accordance with the protocol should be documented in this termination record. After terminating the study patients should be treated according to their medical needs.

The follow-up period should be limited independent of the adverse event to 30 days after the treatment phase has stopped. In case of minor adverse events, a phone call to the patient may be acceptable. If necessary, additional safety investigations and queries could be required during and after this time period.Follow-up information on the outcome must be recorded on the respective AE page in the CRF. All other information has to be documented in the source documents. Source data information has to be available upon request.

Efficacy, Safety And Pharmacokinetic Of Drug-X 1) Asthma Exacerbations

Throughout the run-in and randomized treatment period the patients should be monitored for worsening of their asthma:

 Decrease in FEV1 of ≥ 20% compared to baseline value.

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 Use of≥ 8 puffs/day of salbutamol on any 3 or more days during any 7-consecutive-day period.

 Decrease in morning PEF to ≥ 20% compared to baseline value on any 3 or more days within preceding 7-consecutive-days.

Asthma exacerbations meeting the serious adverse event (SAE) criteria must be reported as such. Signs and symptoms or clinical sequelae resulting from lack of efficacy are to be reported if the fulfill the AE or SAE definitions.Patients experiencing severe asthma exacerbations should be discontinued from the study, indicating exacerbation as the primary reason for withdrawal on the termination record of the CRF. All asthma exacerbations have to be documented in the exacerbation section of the CRF. Additionally, start and end date of the exacerbation has to be documented. All asthma exacerbations, which fulfill any of the serious criteria, must be reported to the sponsor in an expedited manner as serious adverse event and have additionally to be documented in the adverse event section of CRF.

2) Spirometric Evaluation

Spirometry for pulmonary function testing will be performed using centralized spirometry. Spirometers should be provided by the sponsor and should be customized and programmed according to the study requirements.An originally signed and dated printout of lung function measurements has to be stored in the CRF at site. A signed report has to be forwarded to the sponsor together with the original pages of the CRF. Furthermore, electronic data transfer of the obtained spirometry data has to be done on a regular basis as specified in the instruction manual supplied by the spirometry provider.

Spirometry will be performed according to recommendations of the ATS/ERS consensus guidelines on lung function testing. Adherence to acceptability and reproducibility criteria are automatically checked by the spirometer. Additionally, comprehensive manual checks should be performed. Calibration should be done as specified by the spirometry provider.

Table1. Parameters of Spirometry Parameter Descriptions

FEV1 Forced Expiratory Volume in the first second FVC Forced Vital Capacity (expiratory)

FEV/FVC Ratio of Forced Expiratory Volume after one second to Forced Vital Capacity

FEF25-75% Forced Expiratory Flow 25-75%

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FEV6 Forced Expiratory Volume in the first six seconds

FEV/FEV6

Ratio of Forced Expiratory Volume after one second to Forced Expiratory Volume after six seconds

PEFR Peak Expiratory Flow Rate

The following rules will apply for the selection of spirometry data:

FEV 1: Highest value from a minimum of 3 technically acceptable efforts. Should be within 150ml of the next highest, technically acceptable effort; for subjects with FVC < 1.0L this value is 100ml. if the difference is larger, up to 8 measurements should be made.

FVC: Highest value from a minimum of 3 technically acceptable efforts. Should be within 150ml of the next highest, technically acceptable effort; for subjects with FVC < 1.0L this value is 100ml. if the difference is larger, up to 8 measurements should be made.

FEV/IFVC: Will be calculated from the highest FEV1 and the highest FVC, respectively. The highest FEV1 and FVC values may come from different test curves.

FEF25-75%: Taken from the “best test” curve, defined as the one with the highest sum of

FEV 1 + FVC, that meets acceptability criteria.

Values will be corrected to BTPS (body temperature and pressure, saturated) conditions. Predicted values will be calculated according to the reference values of Crapo and Knudson. For non-Caucasians predicted values for FEV1 and FVC should be obtained by multiplying values by a factor of 0.9.

Pre and Post bronchodilator measurements will be performed at only visit 2 for checking reversibility criteria. Directly after the pre-bronchodilator measurement the patient will inhale 400mcg salbutamol sulfates from an MDI with a spacer, and lung function, measurement is to be repeated after 10-15 min.

Efficacy Results

During the 12 weeks of treatments, Drug –x was superior to placebo. The difference between drug-x and placebo in FEV1, for change from baseline was greatly describing the efficacy. For other lung function parameters (FVC, FEV1 and PEF) similar effects were observed that Drug-x was superior to placebo.

SAFETY

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arm, then the DMC would have to strongly consider termination of the study. This evaluation has to be made in consideration of risk/benefit. In many cases, the experimental arm could cause serious adverse events (e.g. chemotherapy), but the resulting improvement in survival outweighs these adverse events.

Adverse events

The well-being of the patients should be ascertained by neutral questioning (“How are you?”) and by the investigator. The investigators is responsible for all adverse events occurring during the course of the study and are reported, including the start date of occurrence, intensity, course of adverse event including outcome relationship to study medication, and any treatment required. The investigator determined whether or not the event is related to the study medication and whether the event is serious.

PharamacokineticOf Drug-X

After oral administration, the Drug-x was extensively metabolized by hepatic CYPs using cDNA expressed p450 isoforms. Among the drug metabolizing hepatic CYPs tested, CYP3A4 was found to catalyze the drug-x in human liver microsomes. After oral administration, drug-x is rapidly and almost completely absorbed: Cmax is reached in more than 1 hour, 1.3 to 1.8 hours in multiple rising dose study in humans. Drug-x has a high absolute bioavailability of 79% when administered orally as an immediate release tablet. In adults, the apparent terminal half-life of drug-x ranges from 13h to 17h after single dose and 12h to 19h after multiple doses. Drug-x N-oxide has an apparent terminal plasma t1/2 of about

13h to 18h after sinlge dose and 14h to 21h after multiple doses.

Drug-x is extensively metabolized by CYP3A4 isozymes to the major, pharmacologically

active N-oxide metabolite, which contributes considerably to the total PDE4 inhibition, i.e. biological activity of Drug-x in vivo. The N-oxide metabolites of Drug-x is found in mice, rats, dogs, monkeys and humans transformed mainly to its N-oxide and reduced back to drug-x before edrug-xcretion. These metabolites were not detected in the plasma from any of the animal species analyzed by HPLC.

Toxicity of Drug –x

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RESULTS AND DISCUSSION

Clinical trials involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug developmental process will normally proceed through all four phases over many years. If the drug successfully passes through Phases I, II, and III, it will be approved by the regulatory authority for use in the general population. Phase IV are „post approval studies‟.

TABLE 2.Plan of Work of all the Visits

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Screeni ng Randomize Day 1 Week 1 Week 3 Week 5 Week 7 Week 9 Week 12 Week (follow up) Eligibility Assessments Informed consent  Establish study- qualifying FEV1  Reversibility (>12% increase in FEV1)  Demography, Medical

history & concurrent disease

 Pregnancy test  Serology (including

HIV & hepatitis B&C)  Efficacy Assessments Spirometry at the clinic

(FEV, FVC, PEF)         Daily spirometry with

peak flow meter (PEF in the dairy)

       

Asthma symptom score

(dairy)        

Salbutamol (dairy)         Pharmacodynamics sampling (sputum & blood)

Blood & sputum, neutrophils &eosinophils

 

Induced sputum

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Eye examination    Vital sign (pulse, blood

pressure)          12-lead ECG          Safety laboratory tests        Adverse events         

FVC – Forced Vital Capacity (the maximum volume of air exhaled after maximum inhalation)

FEV1 – Forced Expiratory Volume in 1sec (maximum volume of air exhaled out in first 1sec after forceful inhalation.

The current therapies for asthma are suboptimal since they are unable to determine the downward trend in pulmonary function. Many new compounds are being discovered, and a subset of these is tested in humans. Until major findings occur to further our understanding of asthma and surrogate markers become available, the hopes reside on the new long acting bronchodilators and anti-inflammatory medications either inhaled or oral. PDE4 inhibitors appear to be the first candidates to be added to the COPD therapies in the near future.

COPD is a common, deadly, yet treatable condition that can be seen by every family physician. There are many options available to reduce symptoms and improve the availability of patients to function normally. Drug-x may be an additional option in the treatment of asthma and COPD due to its ease of administration and a seemingly favorable adverse event profile. However, more research is needed to solidify Drug-x‟s place in therapy.Drug-x is selective phosphodiesterase-4 inhibitor which offers anti-inflammatory and immunomodulatory effects and it was proved by other studies. Office spirometry in the primary care setting can be most helpful for the detection and management of asthma and COPD.

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patients who received the Drug-x shows marked improvement in spirometry parameters from visit V1 to visit Vend. Drug-x has significant safety profile and it can be used for management of asthma. The previous studies and this current study indicate that the Drug-x has good efficacy and safety profile and it can be used to manage the asthma in future.

ACKNOWLEDGEMENT

The authors would like to express sincere and heartfelt gratitude to our guide, Principal Prof. Dr. Mathew George, and Prof. Dr. Lincy Joseph for the support and contribution throughout our study.We also thank all the staffs and Authorities for providing all the necessary facilities and help during this study.

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