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, omalizumab or placebo. The study is designed to determine if QGE031 is superior
to placebo, when added to high daily dose ICS plus LABA (GINA treatment 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.
2 Study objectives
2.1 Primary and key secondary objectives
2.1.1 Primary objective
To evaluate the efficacy of QGE031 240 mg s.c. every two weeks (treatment arm A1, see
Figure 3-1) compared to matched placebo (treatment arm A2) when added to existing asthma
therapy by comparing the responder rates (response defined as a decrease of 0.5 or more of
the ACQ7 score from baseline) following 16 weeks treatment in patients inadequately
controlled on high dose inhaled corticosteroids plus long-acting β2agonists (GINA treatment
step 4). Inadequate control is defined as an ACQ7 score of ≥1.5 at the end of the run-in epoch
(Juniper et al, 2006).
2.1.2 Key secondary objective
In the active comparative component (treatment arms A1 and B1), to evaluate the efficacy 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 (response defined as a decrease of 0.5 or more of the ACQ7 score from baseline)
following 16 weeks treatment in patients inadequately controlled on high dose inhaled
corticosteroids plus long-acting β2agonists (GINA treatment step 4). Inadequate control is
defined as an ACQ7 score of ≥1.5 at the end of the run-in epoch (Juniper et al, 2006).
2.2 Secondary objectives
To assess the efficacy of QGE031 (240 mg s.c. every 2 weeks) versus placebo (every 2
weeks) and omalizumab (administered as per locally approved dosing tables), when added to
high dose ICS plus LABA, in terms of:
• ACQ score after 4, 8, 12, and 16 weeks of treatment and at week 28 (follow-up), with
respect to change from baseline in ACQ scores.
• Proportion of patients with a change from baseline in ACQ score less than -1.1 at week 16.
• AQLQ scores with respect to change from baseline after 16 weeks of treatment and at
week 28 (follow up).
• Day time and night time rescue medication use, and total daily rescue medication use, as
assessed by mean day time and mean night time SABA use (short acting β2-agonist)
recorded between clinic visits i.e. weeks 1-4, 5-8, 9-12, 13-16, and 17 to 28 (follow-up).
To evaluate the safety and tolerability of QGE031 particularly in regard to ECG, laboratory
tests, vital signs, adverse events and injection site reactions, during 16 weeks of treatment and
12 weeks of follow up.
2.3 Exploratory objectives
In treatment arms A1, A2 and B1, to explore the efficacy of QGE031 (240 mg s.c. every 2
weeks) versus matched placebo and omalizumab (administered as per locally approved dosing
tables), when added to high dose ICS plus LABA, in terms of:
• Mean ACD score during the 7 days prior to weeks 4, 8, 12, 16 and 28 (follow up), with
respect to change from baseline in ACD symptom score.
• Trough FEV1 measured at the clinic visits prior to dosing after 4, 8, 12 and 16 weeks of
treatment, and at follow-up
• PEF (AM and PM) as assessed by mean morning and mean evening PEF (peak expiratory
flow) recorded between clinic visits i.e. weeks 1-4, 5-8, 9-12, 13-16, and 17 to 28 (followup)
To perform exploratory pharmacogenetic assessments to examine whether individual genetic
variation in genes relating to drug metabolism, asthma, and the drug target pathway confer
differential response to QGE031.
To explore the potential utility of other biomarkers (as specified in Section 6.6.3) with respect
to 1) prediction of patient response to therapy, and 2) identification of patients at risk of
anaphylaxis and 3) to assess the cellular impact of IgE suppression, including assessing the
impact on mast cell activity and assessing the impact on basophil activation.
To explore in all dose regimens of QGE031, (240 mg q2w, 240mg q4w, 180 mg q2w, 120mg
q2w, 36 mg q2w and 12 mg q2w) placebo and omalizumab (all treatment arms A to G):
• Correlation between ACQ and ACD
• Incidence rate of clinically significant exacerbations during 16 weeks treatment and 12
weeks follow up
• Time to first exacerbation
• The change in exhaled nitric oxide fraction (FeNO) as measured after 8 and 16 weeks of
treatment
To explore in the dose ranging component, for the 6 dose regimens of QGE (treatment arms A,
and C to G): (Placebo, 12 mg q2w, 36 mg q2w, 120 mg q2w, 180 mg q2w, 240 mg q2w and
240 mg q4w)
• Pharmacokinetics and pharmacodynamics
• dose response with respect to efficacy and safety

 

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):
• Signed written informed consent before any assessment is performed, including any
adjustments to asthma medication at Visit 1.
• Male and female adult patients aged ≥18 – ≤75 years.
• Patients with a diagnosis of asthma (according to GINA 2011 guidelines) for a period
of at least 24 months prior to Visit 1.
• 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 or a
depo-injectable dose of corticosteroids, or that required hospitalization or emergency
room (ER) visit.
• FEV1 of ≥ 40% and ≤ 80% of the predicted normal value for the patient, after
withholding bronchodilators1 at Visit 101. If FEV1 is between 80-85% of the patient’s
predicted normal value, a one-time re-testing may be considered.
• 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
o 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
months5 years prior to Visit 12.
- Alternatively, patients may be permitted to enter the study with a historical
positive bronchoprovocation test that was performed within 5 years prior to Visit 1.
o 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) or historical positive bronchoprovocation test is not available:
- The reversibility test may be repeated only once prior to randomization.
• Body mass index (BMI) must be within the range of 18 to 35 40 kg/m2 inclusive.
• 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.
• 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.
• 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.
• 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). (Social occasional smokers, i.e. 1-2 cigarettes at
social occasions, may be included).
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 within the previous 10 years, 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 (non-clinically
significant bronchiectasis may be allowed provided recent (within 3 months prior to Visit
1) CT scan proof is available), 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 ≥78% 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 Visit 101, 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 Visit 101.
19. With history of severe renal failuredisease or creatinine level above the 1.5x ULN at runin
Visit 101.
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 (either
Visit 101 or Visit 102) (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 Visit 101.
23. Patients who have a clinically significant ECG abnormality prior to randomization (Visit
102).
24. With a history of schistosomiasis, orPatients with a stool examination positive for ova or
parasites (at run-in),; re-screening may be considered if a repeat stool examination is
negative following treatmentor 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 Visit 101 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.