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the Efficacy and Safety of Dupilumab in Severe Asthma Cases

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08/02/20 Medical Reference this

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An Article Critique on The Primary Research of the Efficacy and Safety of Dupilumab in Severe Asthma Cases

Effectiveness of Dupilumab in Treating Glucocorticoid-Dependent Severe Asthma

 Asthma is a complex, chronic disorder that can cause debility in the young, as well as in the older adult populations. Asthma is categorized as an inflammatory disorder of the airways in which many cells and cellular elements play a role: Mast cells, eosinophils, neutrophils, T-lymphocytes, macrophages, and epithelial cells all take a part of the response that can cause a sudden onset of symptoms and can cause fatal exacerbations (Guidelines for the Diagnoses and Management of Asthma, 2007).

Asthma symptoms are recurring and variable in nature; as symptoms stem from airflow obstruction, bronchial hyperresponsiveness, and underlying inflammation (Guidelines for the Diagnoses and Management of Asthma, 2007). The goal of asthma treatment is asthma control (Guidelines for the Diagnoses and Management of Asthma, 2007), and in severe, persistent cases of asthma, systemic corticosteroids are used. Corticosteroids are used in short-term therapy and as long-term therapy interventions to help control those symptoms (Guidelines for the Diagnoses and Management of Asthma, 2007). The concern is the effects that systemic corticosteroids have on body systems, so a medication that providers can prescribe to help reduce the use of oral glucocorticoids is needed.

Overview of Current Therapy

 Once diagnosed with asthma, the next steps are to assess the impairment and risk then to determine the initial treatment (Guidelines for the Diagnoses and Management of Asthma, 2007). Lung function measures by spirometry must be obtained in order to develop a baseline (Guidelines for the Diagnoses and Management of Asthma, 2007).  Spirometry readings should be attained at least every 1–2 years, as indicated and more frequently for not-well-controlled asthma (Guidelines for the Diagnoses and Management of Asthma, 2007).

 Nonpharmacological care for the patient with asthma includes self-monitoring in order to self-assess the level of asthma control and to be able to find signs of worsening asthma (Guidelines for the Diagnoses and Management of Asthma, 2007). Peak flow monitoring is particularly helpful for patients who have difficulty perceiving symptoms (Guidelines for the Diagnoses and Management of Asthma, 2007). Providers should help the patient to use written asthma action plans that help the patient to know the differences between long-term control medications and the quick-relief medication usage, and how to take medications correctly (Guidelines for the Diagnoses and Management of Asthma, 2007). The patients are also educated to avoid environmental factors that may worsen their asthma symptoms (Guidelines for the Diagnoses and Management of Asthma, 2007).

 Monitoring is also a part of the care of a patient with asthma, as it is a condition in which the symptoms are highly variable (Guidelines for the Diagnoses and Management of Asthma, 2007). A patient with asthma should be seen at 2- to 6-week intervals while gaining control (Guidelines for the Diagnoses and Management of Asthma, 2007).  A patient within the step of care treatments should be seen between one- and six-month intervals (Guidelines for the Diagnoses and Management of Asthma, 2007).

 Initial pharmacological therapy involves the stepwise approach that expands into six steps (Guidelines for the Diagnoses and Management of Asthma, 2007).  Medications are set within the six steps of care (Guidelines for the Diagnoses and Management of Asthma, 2007). Inhaled corticosteroids (ICSs) continue as preferred long-term control therapy for all ages, a combination of long-acting beta2-agonist (LABA) and ICS is another option, and Omalizumab is recommended for adults who require step 5 or 6 care which is severe asthma (Guidelines for the Diagnoses and Management of Asthma, 2007).

 Treatment for long-term control of severe-persistent asthma symptoms with glucocorticoids has been used to control a further decrease in peak flow, cough, breathlessness, wheezing and chest tightness (Edmunds & Mayhew, 2014). The use of systemic glucocorticoids, although helpful, can also harm multiple body systems (Edmunds & Mayhew, 2014). Some of those concerns are hypertension; thrombophlebitis; thromboembolic events; loss of muscle mass; necrosis of femoral and humeral heads; spontaneous fractures; paresthesia; sodium and fluid retention; glaucoma and posterior subcapsular cataracts, to name a few (Edmunds & Mayhew, 2014).

To help reduce the use of systemic glucocorticoids for control of persistent, severe asthma, current research is focused on finding the efficacy and effectiveness of a new medication: dupilumab. Dupilumab (Dupixent) is an interleukin antagonist that reduces inflammation and alters the immune response (Epocrates, 2019). It comes in an injectable form: a pre-filled syringe of a dose of 200 mg per 1.14 mL and a pre-filled syringe dose of 300 mg per 2 mL (Epocrates, 2019). Indications for use are for moderate to severe asthma (adjunct treatment) and with PO corticosteroid-dependent asthma patients.

One study, in an effort to analyze a new treatment for asthma, looked at 210 patients with oral glucocorticoid -treated asthma. That study is the subject of this paper. The clinical trial was used to discover if the addition of dupilumab to the participant’s medication regime for the control of severe asthma, helped to reduce the use of their oral glucocorticoids. The study also was aimed at discovering if dupilumab use helped to reduce exacerbations of their asthma symptoms.

Analysis

The research study: Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma, was conducted as an international, randomized, double-blind, placebo-controlled, phase 3 trial that utilized 210 patients with the trial ending after 24 weeks (Rabe et al., 2018).  The participants were dependent upon oral glucocorticoid–treatment for control of their asthma symptoms (Rabe et al., 2018).  The participants were chosen randomly: some receiving the add-on medication dupilumab while others did not (Rabe et al., 2018). Dupilumab 300 mg every two weeks for 24 weeks was administered to one group, while the second group received a placebo every 2 weeks for 24 weeks (Rabe et al., 2018). Adjustment periods of the glucocorticoid doses (a downward adjustment) were conducted in order to monitor the effectiveness of dupilumab (Rabe et al., 2018). The oral glucocorticoid dose-adjustment period lasted three to up to ten weeks and then was followed by a 1:1 randomization to receive dupilumab or a placebo for a 24-week period (Rabe et al., 2018). The goal of the study was to find the percentage reduction in the glucocorticoid dose at week 24 (Rabe et al., 2018). The intervention period consisted of a 4-week induction period, and during this time, the adjusted oral glucocorticoid dose was continued (Rabe et al., 2018).  The second step, weeks 4 to 20, used a 16-week period of reduction in oral glucocorticoid use (Rabe et al., 2018). The 16-week period consisted of glucocorticoid dose adjustments that staggered every 4 weeks according to their protocol-prespecified algorithm (Rabe et al., 2018). The next step in the research was a 4-week maintenance period (Rabe et al., 2018). This maintenance period had the participants continue the glucocorticoid dose that was established at week 20 (Rabe et al., 2018). After the intervention period was conducted, a 12-week evaluation period ensued (Rabe et al., 2018).

Criteria for participants included: ages 12 years of age or older who had been diagnosed with asthma by a physician, for 1 year or more, and who had been receiving treatment with regular systemic glucocorticoids in the previous 6 months (Rabe et al., 2018). Other criteria included were: during the 4 weeks before screening, the participant’s treatment had to include a high-dose inhaled glucocorticoid use that was in combination with up to two controllers for at least 3 months, a forced expiratory volume in 1 second before bronchodilator use of 80% or less of the predicted normal value, and/or a hyperresponsiveness episode documented in the last 12 months before the screening visit (Rabe et al., 2018). Participants were excluded if they were less than 12 years of age, if they had a diagnosis of obstructive pulmonary disease or a lung disease that would impair lung function, patients who required 12 puffs or more of their rescue inhalers, and patients with a smoking history or current smoking status (Rabe et al., 2018). 

Efficacy is the strength of the research. The effectiveness, or efficacy, of this trial, was shown by basing and comparing the percentage of the reduction of the oral glucocorticoid doses compared to the baseline up to week 24 and that the participant’s asthma symptoms were controlled (Rabe et al., 2018). The researchers also have shown effectiveness by secondary end points such as the assessment of asthma control with a reduction from their baseline use of an oral glucocorticoid of 50% (Rabe et al., 2018). End-point efficacy included rates of severe exacerbation of symptoms, a hospitalization, or an emergency department visit, or an absolute change in their baseline spirometry readings (Rabe et al., 2018).  In regards to statistical methods, “The primary efficacy endpoint was analyzed using an analysis of covariance (ANCOVA) model. The model included the percentage reduction of oral glucocorticoid dose at Week 24 as the response variable, and treatment groups, optimized glucocorticoid dose at baseline, regions (pooled countries), and baseline eosinophil level subgroups (≥150 cells/µL, <150 cells/µL,) as covariates” (Rabe et al., 2018, para 4).

Strengths of this research trial are many, as all aspects of a scholarly experiment are present. This trial was conducted as an international, randomized, double-blind, placebo-controlled, phase 3 trial that utilized 210 patients with the trial ending after 24 weeks (Rabe et al., 2018).  In relation to the international aspect; Argentina, Belgium, Brazil, Canada, Chile, Italy, and the United States are some example areas that were involved (Rave et al., 2018). The trial was randomized meaning that “each individual has an equal probability of being selected from the population, ensuring that the sample will be representative of the population” (Creswell & Creswell, 2018, p. 250). A double-blind trial is an experimental procedure in which neither the subjects of the experiment nor the persons administering the experiment know the critical aspects of the experiment (thefreedictionary.com, 2019). Placebo-controlled experiment “is a comparative experiment where the comparator treatment is a placebo treatment and is given to a placebo-controlled group member” (Mellis, n.d., para 1). A phase-3 trial is a clinical trial that is “designed to demonstrate the potential advantages of the new therapy over other therapies already on the market; safety and efficacy of the new therapy are studied over a longer period of time” (thefreedictionary.com, n.d., para 1).  Lastly, the number of participants in the study shown to be a large random sampling.

This research study used three phases. The first phase, after the screening, participants were randomly assigned to receive the dupilumab injection while others received the placebo (Rabe et al., 2018). The second phase trialed the doses that were effective and safe in controlling asthma symptoms; with the lower the dose, the better (Rabe et al., 2018). The third phase went into an extensive study so that the researchers could define any adverse side effects and long-term therapeutic effects (Rabe et al., 2018).

In comparison to the group of participants who received the placebo, the group that received the dupilumab injection shown a reduction in the need for oral glucocorticoids- 70.1%, as compared to the placebo group of 41.9% who still used such (Rabe et al., 2018). In relation to adverse side effects, the dupilumab group shown more transient blood eosinophilia concerns as compared to the placebo group, along with higher injection site reactions as well (Rabe et al., 2018).

Study Results

The study results show that use of dupilumab in a patient population greater than 12 years of age who are steroid dependent for control of asthma symptoms could benefit from its use. The clinical trial showed that even though participants had major glucocorticoid-dose reductions, the overall population of dupilumab treated patients shown a severe exacerbation rate that was 59% lower than that in the placebo group (Rabe et al., 2018). The spirometry results also shown higher results as compared to the placebo group (Rabe et al., 2018).

Case Study

 Workshop two in Advanced Pharmacology, we focused on the management of asthma.

Our discussions focused on respiratory pharmacology, class respiratory case studies, and an individual case study/dropbox assignment related to an asthma case study. My case study was a 19-year-old female with a diagnosis of moderate-persistent asthma of 12 years who complained of her asthma acting up. She also felt that she has missed too much school due to asthma concerns. Her medications included: Proventil HFA MDI 2 puffs prn; Flovent 44mcg one puff BID and Albuterol nebulization 2.5mg in 3ml NS prn. In contrast to this study, she was not in the severe stages of asthma and had not needed an oral glucocorticoid before that point in time.

In order for my patient in the case study above to be able to take dupilumab, she would have to be dependent upon an oral glucocorticoid for management of her asthma symptoms. A case study based upon Workshop Two in Advanced Pharmacology will be used as a base for a created case study that utilizes dupilumab. I would be comfortable administering this medication, but I would have to monitor her very closely. I would encourage her to communicate any changes in her health status during this period of adjustment, so a therapeutic, open relationship must be developed.

Case Study

CC:  “My feet have been swelling a lot since I was prescribed prednisone. I’ve been on Prednisone for years, but my swelling is getting worse”.

HPI:  AW is a 53 yof who presents to the health clinic complaining of worsening pedal edema.  

PMH:
Severe persistent asthma for 12 years-oral glucocorticoid dependent.

FH:  One sibling age 48 in good health. Mother passed away 15 years ago from a MVA. Father passed away last year from CHF complications.

SH:  No alcohol or tobacco use.  The patient is a cashier, lives in her own home alone. 

Medications:
Proventil HFA MDI 2 puffs prn
Flovent 44mcg one puff BID
Albuterol nebulization 2.5mg in 3ml NS prn
Prednisone 60 mg daily

Allergies: 
Aspirin (urticaria)

ROS:  Unremarkable except for 3+ pedal edema.

Physical Exam:
GEN:  Worried-appearing Caucasian female in no distress. Skin
VS:  BP 138/82, HR 82, RR 20, T 98.6, wt 140 lb
CHEST:  CTA
CV:   regular rhythm; NMRG

Peak Flow: 340 L/min; her baseline, oxygen saturation 94% RA.

LABS: All WNL

Problem

Subjective/Objective Information

Assessment/Plan

Pedal Edema secondary to long-term use of prednisone.

Subjective

  • My feet have been swelling a lot since I have been on Prednisone.
  • It’s getting worse.
  • I’ve been on Prednisone for years.

Objective

  • 3+ Pedal edema
  • Prednisone dependent severe asthma diagnosis
  • Current medications are: Proventil HFA MDI 2 puffs prn
    Flovent 44mcg one puff BID
    Albuterol nebulization 2.5mg in 3ml NS prn
    Prednisone 60 mg daily

Assessment:

53 yof with complaints of pedal edema (shown at 3+ today) that has progressively worsened over a period of time. LCTA, asthma under control, BP WNL. Current medication: Proventil HFA MDI 2 puffs prn,
Flovent 44mcg one puff BID,
Albuterol nebulization 2.5mg in 3ml NS prn, and
Prednisone 60 mg daily.

Asthma is severe and she is prednisone dependent.

Pharmacological Plan of Care:

  • Stop the current prescription of Prednisone as written.
  • Start tapering prednisone:

Days 1-7 take 60 mg by mouth daily for 7 days then stop.

Days 8-14 take 40mg by mouth daily for 7 days then stop.

Days 15-21 take 30 mg daily by mouth ongoing.

  • Administer 600 mg dupilumab SC on day 7 of the start of the tapering of prednisone (RTO for the initial injection).
  • Start dupilumab SC injections Q2W after the initial starting dose.

Nonpharmacological Plan of Care:

  • When able to, elevate legs above heart level.
  • Wear comfortable shoes that can stretch during periods of increased edema.
  • Lifestyle monitoring (be careful of sodium intake).

Goals:

  • The patient will show no acute exacerbations of asthma that send her to the emergency department.
  • The patient will show no severe adverse effects from the start of dupilumab.
  • Pedal edema will resolve.
  • Asthma symptoms will be controlled with a reduction in oral prednisone and use of adjunct SC injections of dupilumab.
  • Peak flow readings will remain close to her baseline of 340L/min.

Monitoring:

  • Call the office if signs and symptoms of an asthma exacerbation are present.
  • Monitor peak flow/spirometry readings three times a day and as needed during this adjustment period. This will allow you to know if an asthma exacerbation is coming on.
  • Monitor for adverse side effects from dupilumab (injection site irritation and an increase in eosinophils).
  • Monitor for a hypersensitive reaction during the initial dose and thereafter.
  • RTO in 7 days with your dupilumab so that we can administer the initial dose in the office.
  • Monitor for uncontrolled asthma symptoms due to the decrease in prednisone.
  • Monitor for a decrease in pedal edema.
  • See your optometrist routinely and let him/her know that you are taking dupilumab.
  • Monitor her for any eye concerns while in the office.
  • *No routine tests are needed for dupilumab (Epocrates, 2019).
  • Monitor for compliance of treatment.

Patient Education:

  • How to administer SC injections.
  • Side effects of dupilumab: irritation at injection sites, hypersensitivity rxn, keratitis, conjunctivitis, blepharitis, ocular pruritus, dry eyes or oropharyngeal pain.
  • If irritation develops at the injection site, may apply cool cloths as needed.
  • May take OTC acetaminophen as directed on label for pain at the injection site.
  • Stay away from NSAIDS as they can contribute to sodium retention/edema as well.

Conclusion

 In conclusion, the study found that use of dupilumab was both effective and safe. The study results can change current therapy by allowing a decrease in oral glucocorticoid usage. The prescriber must be aware to closely monitor the patient for exacerbations, and emergency room visits related to severe asthma exacerbation symptoms. The provider must also monitor adverse side effects such as irritation at injection sites and an increase in eosinophils.

Dupilumab therapy was effective, as proven by reducing the use of oral glucocorticoids in the participants (Rabe et al., 2018). Dupilumab was found safe, as the only side effects noted were irritation at the injection site and chances of elevated eosinophils (Rabe et al., 2018). The long-term study phase also showed no severe adverse side effects that were at a high degree to where it should not be marketed (Rabe et al., 2018).  Dupilumab can be an effective and safe medication to help reduce glucocorticoid usage that can harm multiple body systems.

References

  • Creswell, J.W., & Creswell, J.D. (2018). Research design: Qualitative, quantitative, and mixed methods approach. (5th ed.). Thousand Oaks, CA: SAGE Publications
  • Dupilumab. (2019). In Epocrates (Version 19.2). [Mobile Application Software]. Retrieved from http://epocrates.com/mobile/iphone/essentials 
  • Edmunds, M. W., & Mayhew, M. S. (2014). Pharmacology for the Primary Care Provider (4th ed.). St. Louis, MO: Elsevier Mosby
  • Freedictionary.com (n.d.). Double-blind placebo. Retrieved May 26, 2019 from https://www.thefreedictionary.com/double-blind+study
  • Freedictionary.com (n.d.). Phase study. Retrieved May 26, 2019 from https://medical-dictionary.thefreedictionary.com/phase+study
  • Gabormelli.com. (n.d.).  Placebo-controlled experiment. Retrieved May 26, 2019 from http://www.gabormelli.com/RKB/Placebo-Controlled_Experiment
  • Guidelines for the Diagnoses and Management of Asthma. (2007). Asthma definitions and implications. Retrieved May 25, 2019 from https://www.nhlbi.nih.gov/sites/default/files/media/docs/asthsumm.pdf
  • Prednisone. (2019). In Epocrates (Version 19.2). [Mobile Application Software]. Retrieved from http://epocrates.com/mobile/iphone/essentials 
  • Rabe, K.F., Parameswaran, N., Brusselle, G., Maspero, J.F., Castro, M., Sher, L.,…Teper, A. (2018). Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. New England Journal of Medicine. 378, 2475-2485. doi: 10.1056/NEJMoa1804093
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