QGE031in Asthma Patients

Overview

Status: Not yet recruiting
Keywords: Asthma
IRB Number: 00062133
Specialty: Allergy and Clinical Immunology
Sub Specialties: Environmental Allergy

Brief Summary

The purpose of this study is to collect efficacy and safety data in asthma patients not adequately controlled with high-dose ICS plus long-acting β2-agonist who are receiving QGE031(study drug), omalizumab or placebo. The study is designed to determine if QGE031 is superior to placebo, when added to high daily dose ICS plus LABA (Global Initiative for Asthma GINA step 4).

Asthma control will be the primary endpoint using the Asthma Control Questionnaire (ACQ). The study will also allow comparison of the safety and efficacy of QGE031 compared to omalizumab in this population.

Data collected during this study will be used to support decision making related to further development

of QGE031 for the asthma indication. The study will also provide data to aid selection of doses for

further evaluation and provide information on patient reported outcome (PRO) tools and potential

biomarkers which may be included in future studies.

 

Study objectives

Primary objective:

To evaluate the efficacy of QGE031 240 mg s.c. every two weeks compared to matched placebo when

added to existing asthma therapy by comparing the responder rates* following 16 weeks treatment in

patients inadequately controlled** on high dose inhaled corticosteroids plus long-acting β2agonists

(GINA treatment step 4).

Key secondary objective:

To evaluate the superiority of QGE031 240 mg s.c. every two weeks compared to omalizumab

(administered as per locally approved dosing tables) when added to existing asthma therapy by

comparing the responder rates* following 16 weeks treatment in patients inadequately controlled** on

high dose inhaled corticosteroids plus long-acting β2agonists (GINA treatment step 4).

* Response is defined as a decrease of 0.5 or more of the ACQ7 score from baseline)

**Inadequate control is defined as an ACQ7 score of ≥1.5 at the end of the run-in epoch (Juniper et al,

2006).

Other Secondary Objective:

Though the pharmacogenetic portion of the study will not be implemented at the University of Utah, an exploritory pharmacogenetics research study is planned as a part of the overall study at other sites with the objectives of identifying inherited genetic factors which may (1) be related to asthma, (2)

predict response to treatment with QGE031, (3) predict relative susceptibility to drug-drug

interactions, or (4) predict genetic predisposition to side effects. We hope to develop a better

understanding of asthma and how subjects respond to QGE031.

Principal Investigator: Gerald Gleich
Department: Dermatology
Co Investigator: Rafael Firszt

Contact Information

Name:Kaylynn Shakespear
Phone: (801) 587-8804
Email: Kaylynn.Shakespear@hsc.utah.edu

Inclusion Criteria

Patients eligible for inclusion in this study have to fulfill all of the following criteria:

For all patients (treatment arms A to G):

1. Signed written informed consent before any assessment is performed, including any adjustments to asthma medication at Visit 1.

2. Male and female adult patients aged 18 – 75 years.

3. Patients with a diagnosis of asthma (according to GINA 2011 guidelines) for a period of at least 24 months prior to Visit 1.

4. A documented history of at least one asthma exacerbation in the previous 12 months that has a documented treatment with systemic corticosteroids for at least 3 days.

5. FEV1 of 40% and 80% of the predicted normal value for the patient, after withholding bronchodilators1.

6. Patients must demonstrate an increase in FEV1 of 12% and 200 mLs within 30 minutes after administration of 400 μg salbutamol/albuterol (or equivalent dose) prior to randomization2.

All patients must perform a reversibility test at Visit 101

If reversibility is not demonstrated at Visit 101:

Patients may be permitted to enter the study with historical evidence of reversibility that was performed according to ATS/ERS guidelines within the 12 months prior to

Visit 12.

If reversibility is not demonstrated at Visit 101 and historical evidence of reversibility is not available (or was not performed according to ATS/ERS guidelines):

The reversibility test may be repeated only once prior to randomization.

7. Body mass index (BMI) must be within the range of 18 to 35 kg/m2 inclusive.

8. Daily treatment with:

At Visit 1: Medium or high dose3 ICS plus a LABA (b.i.d. or equivalent) for 3 months prior to Visit 1*, and

At Visit 201: High dose ICS3 plus a LABA (b.i.d. or equivalent) that has been stable for at least 4 weeks prior to Visit 201.

See Appendix 3 for definitions of “Medium” and “High” dose ICS (per GINA 2011) *Patients receiving medium dose ICS at Visit 1 should be pre-scribed high dose ICS at Visit 101; this dose should then remain stable during the 4 week run-in epoch prior to Visit 201.

9. Asthma which is not adequately controlled on current treatment, as demonstrated by an Asthma Control Questionnaire (ACQ) score of 1.5 (Juniper et al, 2006) at Visit 101 and prior to randomization.

10. Patients should be allergic or atopic to a perennial aeroallergen [house dust mite {dermatophagoides pteronyssinus, dermatophagoides farina], cockroach, mold, cat/dog dander), as diagnosed at Visit 101, prior to entry into the study, by either a skin prick test (3mm diameter above background) or a positive in-vitro specific IgE (e.g. RAST/CAP) test.

11. Compliance with Electronic Peak Flow/ ediary device4 during the run-in epoch (at the investigators judgment the run-in epoch can be extended to collect 14 days of acceptable ePEF/ediary data).

1 Withholding of bronchodilators prior to spirometry: short-acting β2-agonist for 6 hrs and long-acting beta2-agonist (or fixed dose combinations of LABA and ICS) for 24 hours.

2 Where a patient is assessed as eligible based on historical evidence of reversibility, a copy of the original printed spirometry report with relevant spirometry tracings must be available as source documentation.

3 See Appendix 3 for GINA 2011 definition of medium and high dose ICS.

4 Compliance is defined as 85% of the ePEF assessments and 85% of the morning or evening ediary entries completed correctly in the 14 days prior to the randomization. Thresholds will be automatically calculated by the ePEF/ediary device.

Exclusion Criteria

Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.

For all patients (treatment arms A to G):

1. Patients whose baseline serum IgE levels1 or body weight are outside the limits of the locally approved omalizumab dosing table.

1See Section 6.6.1.2 for definition of baseline serum IgE and refer to relevant locally approved omalizumab dosing table in the QGE031B2201 study manual.

2. Who have smoked or inhaled tobacco products within the 6 month period prior to Visit 1, or who have a smoking history of greater than 10 pack years (e.g.10 pack years = 1 pack /day x 10 yrs., or ½ pack/day x 20 yrs.).

3. Who have had an asthma attack/exacerbation requiring a short burst of systemic corticosteroids for at least 3 days within 6 weeks prior to Visit 1.

4. If patients experience an asthma attack/exacerbation requiring a short burst of systemic corticosteroids during screening and run-in they may be re screened 6 weeks after recovery from the exacerbation.

5. Who have had a respiratory tract infection or asthma worsening within 4 weeks prior to Visit 1.

6. If patients experience a respiratory tract infection or asthma worsening during screening and run-in they may be re screened 4 weeks after recovery from their respiratory tract infection.

7. Patients with a history of life-threatening asthma, including a history of significant hypercarbia (pCO2>45mmHg), prior intubation (endotracheal and NIPPV), respiratory arrest, or seizures as a result of asthma.

8. Who have a history of generalized urticarial or who have an acute urticarial episode at time of screening or during run-in. If patients experience an acute urticarial episode at screening or run-in, they may be re-screened once the urticarial has resolved.

9. Patients with evidence upon visual inspection (laboratory culture is not required) of clinically significant oropharyngeal candidiasis during screening and run-in, with or without treatment. Patients may be re screened once their candidiasis has been treated and has resolved.

10. Patients with any chronic conditions affecting the upper respiratory tract (e.g. chronic sinusitis) which in the opinion of the investigator may interfere with the study evaluation or optimal participation in the study.

11. Patients with a history of chronic lung diseases other than asthma, including (but not limited to) chronic obstructive pulmonary disease, bronchiectasis, sarcoidosis, interstitial lung disease, cystic fibrosis, and tuberculosis.

12. Patients with aspirin or other nonsteroidal anti-inflammatory drug related asthma.

13. Patients with elevated serum IgE levels for reasons other than atopic conditions (e.g., parasitic infections, hyperimmunoglobulin E syndrome, allergic bronchopulmonary aspergillosis).

14. Patients with uncontrolled diabetes Type I or uncontrolled diabetes Type II having an HbA1C test result 7% at Visit 101.

15. Patients who have a clinically significant laboratory abnormality that is not compatible with the natural history of atopic asthma at run-in, in the judgment of the investigator.

16. Patients who, either in the judgment of the investigator have a clinically significant condition such as (but not limited to) unstable ischemic heart disease, NYHA Class III/IV left ventricular failure arrhythmia, uncontrolled hypertension, cerebrovascular disease, neurodegenerative diseases, or other neurological disease, uncontrolled hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or ophthalmologic disorder or patients with a medical condition that might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study.

17. Patients with a history of myocardial infarction within the previous 12 months.

18. With a history or current treatment for hepatic disease including but not limited to acute or chronic hepatitis, cirrhosis or hepatic failure or an AST/ALT or INR of more than 1.5x ULN at run-in.

19. With history of renal disease or creatinine level above the ULN at run-in.

20. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.

21. Patients with a history of long QT syndrome or whose QTc measured at run-in (Fridericia method) is prolonged (>450 ms for males and females) and confirmed by a central assessor. (These patients should not be re-screened).

22. Patients who have a clinically significant ECG abnormality at run-in.

23. Patients who have a clinically significant ECG abnormality prior to randomization.

24. With a history of schistosomiasis, or stool examination positive for ova or parasites (at run-in), or travel to an area endemic with schistosomiasis or helminth infection (in the 6 months prior to Visit 1).

25. With a history of immunodeficiency diseases or active hepatitis B or C.

26. Patients with a known hypersensitivity against any constituents of the study drugs or to murine, chimeric, or human antibodies.

27. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift workers will be excluded).

28. Patients who have not achieved acceptable spirometry results at screening in accordance with ATS/ERS criteria for acceptability and repeatability.

29. Patients receiving any medications in the classes listed in (Table 5-2).

30. Patients receiving any Asthma related medications in the classes specified in (Table 5-3) unless they undergo the required washout period prior to Visit 101 and follow the adjustment to treatment program.

31. Patients receiving medications in the classes listed in (Table 5-4) should be excluded unless the medication has been stabilized for the specified period and the stated conditions have been met.

32. Patients receiving immunotherapy (desensitization) for allergies, unless maintenance dose has been administered for at least 3 months prior to Visit 101, and is expected to remain unchanged throughout the course of the study.

33. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives prior to Visit 1, whichever is longer.

34. Previous exposure to QGE031.

35. Patients unable or unwilling to receive sub-cutaneous injections.

36. History of alcohol or other substance abuse in the 12 months prior to Visit 1.

37. Patients with a known history of non-compliance to medication, or who were unable or unwilling to complete a patient diary, or who are unable or unwilling to use Electronic Peak Flow with e-diary device or perform spirometry measurements.

38. No person directly associated with the administration of the study is allowed to participate as a study subject. No family member of the investigational study staff is allowed to participate in this study.

39. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 105 days (= 5 times the terminal half-life) of study medication.

Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 m prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject

Combination of any two of the following (a+b or a+c or b+c)

a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.

b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

In case of use of oral contraception women should have been stabile on the same pill for a minimum of 3 months before taking study treatment.

Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

40. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.