Skip to main content
OpenTrials
Completed

NCT Number: NCT02676076

TRIple in asthMA With uncontRolled pAtient on Medium streNgth of ICS + LABA

Evaluate the superiority of CHF 5993 100/6/12.5 µg Pressurised Metered Dose Inhaler (pMDI) (fixed combination of extrafine beclometasone dipropionate (BDP) plus formoterol fumarate (FF) plus glycopyrronium bromide [GB]) versus CHF 1535 100/6 µg pMDI (fixed combination of extrafine beclometasone dipropionate (BDP) plus formoterol fumarate [FF]), with regard to lung functions parameters and rate of exacerbations as well as safety and health economics outcomes, in adult patients with uncontrolled asthma on medium doses of inhaled corticosteroids in combination with long acting ß2 agonists (LABA).

Completed

Looking for future studies?

Notify Me

Key information

Conditions

Asthma Bronchial Diseases Hypersensitivity Hypersensitivity, Immediate Immune System Diseases Lung Diseases Lung Diseases, Obstructive Respiratory Hypersensitivity Respiratory Tract Diseases

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Chiesi Clinical Trial Site 276814

Rostock, Germany

About this study

This study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines, and following all other requirements of local laws.

From screening to the end of treatment, vital signs were recorded pre-dose at screening and pre- and postdose at all visits during the treatment period; physical examination was performed at all visits; concomitant medications and adverse events (AEs) were recorded, and asthma exacerbations were assessed at all visits; lung function tests were performed (pre-dose for forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) from screening to end of treatment visits, pre-dose for inspiratory capacity and vital capacity and postdose serial spirometry at all visits during the treatment period).

Patients completed the electronic diary from home twice daily from the time of screening until the end of treatment, to record asthma symptoms, treatment compliance, and use of rescue medication. Patients used the electronic peak flowmeter to record peak expiratory flow twice daily from home from the time of screening until the end of treatment.

Asthma Control Questionnaire© (ACQ)-7 was completed at screening and all visits during the treatment period. The EuroQuality of Life-5-Dimensional-3-Level questionnaire, and health economic and outcome assessments were competed at all visits during the treatment period.

Rescue medication (salbutamol 100 μg per inhalation) was permitted throughout the treatment period when absolutely needed; the maximum allowed dose was 8 inhalations/day (800 μg).

An independent Data Safety Monitoring Board was established to provide impartial safety evaluation and assurance for patients.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • History of asthma ≥ 1 year and diagnosed before 40 years old
  • Uncontrolled asthma with double therapy only on medium doses of Inhaled CorticoSteroid (ICS) in combination with Long-acting beta2 Agonist (LABA) with ACQ-7 (Asthma Control Questionnaire) ≥1.5
  • Pre-bronchodilator FEV1 <80% of the predicted normal value
  • Positive reversibility test
  • At least 1 documented asthma exacerbation in the previous year

Exclusion criteria

  • Pregnant or lactating women
  • Diagnosis of Chronic Obstructive Pulmonary Disease (COPD)
  • Patients with any asthma exacerbation or respiratory tract infection in the 4 weeks prior screening
  • Current or ex-smokers (>= 10 packs year)
  • Any change in dose, schedule or formulation of ICS + LABA combination in the 4 weeks prior screening

Treatment and study plan

CHF 5993 100/6/12.5

Drug

BDP=Beclometasone Dipropionate 100µg; FF=Formoterol Fumarate 6µg; GB=Glycopyrronium Bromide 12.5µg.

CHF 1535 100/6 µg

Drug

BDP=Beclometasone Dipropionate 100µg; FF=Formoterol Fumarate 6µg.

Primary outcomes

  1. 1_Change From Baseline in Pre-Dose Forced Expiratory Volume in the First Second (FEV1) at Week 26

    Time frame: Week 0 (pre-treatment, baseline) to Week 26.

    Change from baseline in pre-dose FEV1 was analysed at Week 26 of treatment.

    FEV1=Forced expiratory volume in the first second

  2. 2_Moderate and Severe Asthma Exacerbation Rate Over the 52-Week Treatment Period

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Asthma exacerbation (events): Moderate AND Severe.

    Severe: asthma worsening requiring initiation of treatment with systemic corticosteroids for at least 3 days (courses of corticosteroids separated by ≥1 week treated as separate severe exacerbations).

    Moderate: ≥1 of the following criteria fulfilled and leading to a change in treatment (sustained increase of ≥1 puff of short acting beta 2-agonist [SABA] for 2 consecutive days) as shown below:

    • Nocturnal awakening(s) due to asthma requiring SABA for 2 consecutive nights/increase of ≥0.75 from baseline in daily symptom score on 2 consecutive days; increase from baseline in occasions of SABA use on 2 consecutive days (minimum increase 4 puffs/day);
    • ≥20% decrease in peak expiratory flow from baseline on at least 2 consecutive mornings/evenings or ≥20% decrease in FEV1 from baseline;
    • Visit to the ER/trial site for asthma treatment not requiring systemic corticosteroid.

Secondary outcomes

  1. 3_Change From Baseline in Peak(0-3h) FEV1 at Week 26

    Time frame: Week 0 (pre-treatment, baseline) and Week 26.

    Peak FEV1 was analysed within 3 hours post-dose.

    FEV1=Peak of forced expiratory volume in the first second

  2. 4_Change From Baseline in Morning Peak Expiratory Flow (PEF) Over the 26-Week Treatment

    Time frame: Week 0 (pre-treatment, baseline) to Week 26.

    Change from baseline in the average morning PEF over the 26-Week treatment.

    PEF=Peak expiratory flow; is the volume of air forcefully expelled from the lungs in one quick exhalation.

  3. 5_Severe Asthma Exacerbation Rate Over the 52-Week Treatment Period - Pooled Analysis

    Time frame: The entire treatment period; up to Week 52.

    Severe Asthma Exacerbation Rate over the 52-Week Treatment Period in a pre-specified pooled analysis of 2 pivotal studies CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER).

    The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

  4. 6_Change From Baseline in Peak FEV1 (0-3h) at All Clinical Visits

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Change from baseline in peak FEV1 (within 3 h post-dosing) at all clinical visits.

    Baseline for pre-dose FEV1 was calculated as average of the FEV1 measurements (L) from the visit 2 (V2) Pre45min & V2 Pre15min. If one of the two pre-dose values was missing, the baseline was equal to the available pre-dose value.

  5. 7_Change From Baseline in Pre-Dose FEV1 at All Clinical Visits

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Results show the change from baseline in pre-dose FEV1 at all clinical visits.

  6. 8_FEV1 Response (FEV1 ≥ 100 mL) at Week 26 and Week 52

    Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52.

    Results show the percentage of patients classified as FEV1 responders at both Week 26 and Week 52. FEV1 response: Change from baseline in pre-dose morning FEV1 ≥ 100 mL.

  7. 9_Change From Baseline in FEV1 Area Under the Curve (AUC) (0-3h) Normalised by Time at All Clinical Visits

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Baseline definition: mean of two pre-dose FEV1 measurements at visit 2 (V2).

    Results show the change from baseline in FEV1 area under the curve [AUC] (0-3h) at all subsequent visits (i.e. change from baseline of the AUC of the serial post-dose spirometry assessments till 3h post-dose).

  8. 10_Change From Baseline in the Asthma Control Questionnaire-7 (ACQ-7) Score at All Clinical Visits

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    ACQ-7 Questionnaire.

    Asthma Control Questionnaire-7 (ACQ-7) allows assessment of asthma control in individual patients.

    The ACQ-7 measured asthma symptom control and consists of 7 items: 5 on symptom assessment, 1 on rescue medication use and 1 on lung function (FEV1 % predicted). All seven items are scored on a 7-point Likert scale, with 0 indicating total control (no impairment) and 6 indicating poor control (maximum impairment). The questions are equally weighted and the total score is the mean of the seven items. The first 6 questions of the ACQ-7 were completed by the participant while the last question was completed by the study investigator using data from the Master Scope spirometer.

    Baseline for ACQ-7 was the total score recorded at Visit 2 (Week 0) of the study. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. A negative change from baseline indicates improvement in lung function.

  9. 11_Asthma Control Questionnaire©-7 Response at Week 26 and Week 52

    Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52

    Asthma Control Questionnaire (ACQ) and Asthma Control Questionnaire-7 (QAC-7) are defined in the description of Outcome measure 10 above.

    An ACQ-7 response was defined as change from baseline (Week 0, pre-dose) in ACQ-7 score ≤ -0.5; non-response was defined as change from baseline in ACQ-7 score >-0.5 or missing data.

    Results represent the responders (i.e. change from baseline in ACQ-7 Score ≤ -0.5) at Week 26 and Week 52.

  10. 12a_Change From Baseline in Average Morning PEF (L/Min) Over 52 Weeks of Treatment

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Change from baseline in average MORNING PEF (L/min) over 52 weeks of treatment.

    PEF=Peak expiratory flow; is the volume of air forcefully expelled from the lungs in one quick exhalation.

  11. 12b_Change From Baseline in Average Evening PEF (L/Min) Over 26 and 52 Weeks of Treatment

    Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52.

    Change from baseline in average EVENING PEF (L/min) over 26 and 52 weeks of treatment.

    PEF=Peak expiratory flow; is the volume of air forcefully expelled from the lungs in one quick exhalation.

  12. 13_Number of Patients at Risk of Moderate or Severe Asthma Exacerbation Over 52 Weeks

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Data were analysed for the number of patients at risk of a moderate or severe asthma exacerbation.

    Results show the number of patients who had moderate or severe asthma exacerbation over the 52 weeks treatment period.

  13. 14_Number of Patients at Risk of Severe Asthma Exacerbation in the Pooled Analysis of the Two Pivotal Studies CCD-05993AB1-03 and CCD-05993AB2-02

    Time frame: Week 0 (Baseline) to 52 weeks for both studies in the pooled analysis.

    Data were analysed for the number of patients at risk of a severe asthma exacerbation in the pooled analysis of the two pivotal studies CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER).

    Results show the number of patients who had a severe asthma exacerbation over the 52 weeks treatment period.

    The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

  14. 15_Moderate Asthma Exacerbation Rate Over the 52-Week Treatment Period in the Pooled Analysis of the 2 Pivotal Studies CCD-05993AB1-03 and CCD-055993AB2-02.

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Moderate asthma exacerbation rate over the 52-Week treatment period in the pooled analysis of the 2 pivotal studies CCD-05993AB1-03 (TRIMARAN) and CCD-055993AB2-02 (TRIGGER).

    The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

  15. 16_Number of Patients at Risk of MODERATE Asthma Exacerbation in the Pooled Analysis of the Two Pivotal Studies CCD-05993AB1-03 and CCD-05993AB2-02

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Number of Patients at Risk of MODERATE Asthma Exacerbation in the Pooled Analysis of the Two Pivotal Studies CCD-05993AB1-03 and CCD-05993AB2-02.

    The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

  16. 17_Moderate and Severe Asthma Exacerbation Rate Over the 52-Week Treatment Period in the Pooled Analysis of the 2 Pivotal Studies CCD-05993AB1-03 and CCD-055993AB2-02

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Moderate and severe asthma exacerbation rate over the 52-Week treatment period in the pooled analysis of the 2 pivotal studies CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER).

    Results show the number of participants with moderate and severe asthma exacerbation.

    The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

  17. 18_Number of Patients at Risk of Moderate OR Severe Asthma Exacerbation in the Pooled Analysis of the Two Pivotal Studies CCD-05993AB1-03 and CCD-05993AB2-02

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Time to first moderate or severe asthma exacerbation in the Pooled Analysis of the 2 Pivotal Studies CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER).

    Results show the number of participants with moderate or severe asthma exacerbation.

    The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

  18. 19_Moderate Asthma Exacerbation Rate Over the 52-Week Treatment Period

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Moderate asthma exacerbation rate over the 52-Week treatment period.

  19. 20_Number of Patients at Risk of a MODERATE Asthma Exacerbation

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Data were analysed for the number of patients at risk of a MODERATE asthma exacerbation.

  20. 21a_Change From Baseline in the Average Use of Rescue Medication Over the 26- and 52-Week Treatment Periods

    Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52.

    Change from baseline in the average use of rescue medication over the 26- and 52-Week treatment periods.

    Data was collected through an electronic daily diary from screening to the end of the study.

  21. 21b_Change From Baseline in the Average Use of Rescue Medication in Each Inter-Visit Period

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Results show the change from baseline in the average use (puffs/day) of rescue medication in each inter-visit period.

    Data was collected through an electronic daily diary from screening to the end of the study.

  22. 22a_Change From Baseline in the Percentage of Rescue Medication-Free Days Over the 26- and 52-Week Treatment Periods

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Change from baseline in the percentage of rescue medication-free days in each inter-visit period over the 26- and 52-Week treatment periods.

    Data was collected through an electronic daily diary from screening to the end of the study.

  23. 22b_Change From Baseline in the Percentage of Rescue Medication-Free Days in Each Inter-Visit Period Over the Treatment

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Results show the change from baseline in the percentage of rescue medication-free days in each inter-visit period over the entire treatment.

    Data was collected through an electronic daily diary from screening to the end of the study.

  24. 23a_Change From Baseline in the Average Daily Asthma Symptom Scores Over the 26- and 52-Week Treatment Periods

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Data was collected through an electronic daily diary from screening to the end of the study.

    Results show the change from baseline in the average daily asthma symptom scores over the 26- and 52-Weeks of treatment.

    A day represents data recorded in the evening session of that day plus the data recorded in the morning session of the next day.

    Symptoms considered: cough, wheeze, chest tightness, breathlessness.

    • Morning (night-time asthma symptom score):
    • 0 No symptoms;
    • 1 Mild = Symptoms not causing awakening;
    • 2 Moderate = Discomfort enough to cause awakenings;
    • 3 Severe = Causing awakenings for most of the night/did not sleep at all.
    • Evening (daytime asthma symptom score):
    • 0 No symptoms;
    • 1 Mild = Aware of symptoms, which could be easily tolerated;
    • 2 Moderate = Discomfort enough to cause interference with daily activity;
    • 3 Severe = Incapacitating

  25. 23b_Change From Baseline in the Average Daily Asthma Symptom Scores in Each Inter-Visit Period

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Results show the change from baseline in the average daily asthma symptom scores in each inter-visit period over the entire treatment. Data was collected daily through an electronic diary from screening to the end of the study.

    A day represents data recorded in the evening session of that day plus the data recorded in the morning session of the next day.

    Symptoms considered: cough, wheeze, chest tightness, breathlessness.

    • Morning (night-time asthma symptom score):
    • 0 No symptoms;
    • 1 Mild = Symptoms not causing awakening;
    • 2 Moderate = Discomfort enough to cause awakenings;
    • 3 Severe = Causing awakenings for most of the night/did not sleep at all.
    • Evening (daytime asthma symptom score):
    • 0 No symptoms;
    • 1 Mild = Aware of symptoms, which could be easily tolerated;
    • 2 Moderate = Discomfort enough to cause interference with daily activity;
    • 3 Severe = Incapacitating

  26. 24a_Change From Baseline in the Percentage of Asthma Symptom-Free Days Over the 26- and 52-Week Treatment Periods

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Change from baseline in the percentage of asthma symptom-free days over the 26- and 52-Week treatment periods.

    Data was collected through an electronic daily diary from screening to the end of the study.

    Results show the change from baseline in the average daily asthma symptom scores over the 26- and 52-Week treatment periods. A day represents data recorded in the evening session of that day plus the data recorded in the morning session of the next day.

    Symptoms considered by the questionnaire: cough, wheeze, chest tightness, breathlessness.

    An asthma symptom-free day is a day with total daily asthma symptom score = 0. For a description of the score see outcome measure number 23.

  27. 24b_Change From Baseline in the Percentage of Asthma Symptom-Free Days in Each Inter-Visit Periods

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Results show the change from baseline in the percentage of asthma symptom-free days in each inter-visit periods over the entire treatment.

    Data was collected through an electronic daily diary from screening to end of the study.

    A day represents data recorded in the evening session of that day plus the data recorded in the morning session of the next day.

    Symptoms considered by the questionnaire: cough, wheeze, chest tightness, breathlessness.

    An asthma symptom-free day is a day with total daily asthma symptom score = 0. For a description of the score see outcome measure number 23.

  28. 25a_Change From Baseline in the Percentage of Asthma Control Days Over the 26- and 52-Week Treatment Periods

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Results show the change from baseline in the percentage of asthma control days over the 26- and 52-Week treatment periods.

    Data was collected through an electronic daily diary from screening to the end of the study.

    Scoring of asthma symptoms (overall symptoms, cough, wheeze, chest tightness and breathlessness):

    Morning (night-time asthma symptoms): 0 (no symptoms), 1 (mild - symptoms not causing awakening), 2 (moderate - discomfort enough to cause awakenings) and 3 (severe - causing awakenings for most of the night/did not sleep at all).

    Evening (daytime asthma symptoms): 0 (no symptoms), 1 (mild: aware of symptoms that could be easily tolerated), 2 (moderate: discomfort enough to cause interference with daily activity), 3 (severe: incapacitating with inability to work/take part in usual activity).

  29. 25b_Change From Baseline in the Percentage of Asthma Control Days in Each Inter-Visit Period

    Time frame: Week 0 (pre-treatment, baseline) to Week 52.

    Results show the change from baseline in the percentage of asthma control days in each inter-visit period.

    A day represents data recorded in the evening session of that day plus the data recorded in the morning session of the next day.

    Data was collected through an electronic daily diary from screening to the end of the study

    Scoring of asthma symptoms (overall symptoms, cough, wheeze, chest tightness and breathlessness):

    Morning (night-time asthma symptoms): 0 (no symptoms), 1 (mild - symptoms not causing awakening), 2 (moderate - discomfort enough to cause awakenings) and 3 (severe - causing awakenings for most of the night/did not sleep at all).

    Evening (daytime asthma symptoms): 0 (no symptoms), 1 (mild: aware of symptoms that could be easily tolerated), 2 (moderate: discomfort enough to cause interference with daily activity), 3 (severe: incapacitating with inability to work/take part in usual activity).

Sponsors and collaborators

Lead sponsor

Chiesi Farmaceutici S.p.A.

Industry

Registry information

Official study title

A 52 WEEK, RANDOMIZED, DOUBLE BLIND, MULTINATIONAL, MULTICENTRE, ACTIVE CONTROLLED, 2-ARM PARALLEL GROUP TRIAL COMPARING CHF 5993 100/6/12.5 µg pMDI (FIXED COMBINATION OF EXTRAFINE BECLOMETASONE DIPROPIONATE PLUS FORMOTEROL FUMARATE PLUS GLYCOPYRRONIUM BROMIDE) TO CHF 1535 100/6 µg pMDI (FIXED COMBINATION OF EXTRAFINE BECLOMETHASONE DIPROPIONATE PLUS FORMOTEROL FUMARATE) IN PATIENTS WITH ASTHMA UNCONTROLLED ON MEDIUM DOSES OF INHALED CORTICOSTEROIDS IN COMBINATION WITH LONG ACTING ß2 AGONISTS

Acronym: TRIMARAN

Important dates

Study start
2016
Primary completion
2018
Study completion
2018
First posted
Feb 8, 2016
Registry last updated
Jun 26, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Related clinical trials

Published trials that share one or more normalized conditions with this study.