HypertensionPhase 1NCT00871871

Multiple Dose Effects of Hydrochlorothiazide and Isosorbide Mononitrate on Glucose Homeostasis (MK-0000-117)(Completed)

A Phase 1 study testing Hydrochlorothiazide (HCTZ) and Isosorbide mononitrate (ISMN) in people with Hypertension, run by Merck Sharp & Dohme LLC.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

Search all trials

Trial summary

This study will measure and compare changes in insulin production and sensitivity using the hyperglycemic clamp technique in obese patients with impaired glucose tolerance and hypertension treated with placebo, isosorbide mononitrate (ISMN) or hydrochlorothiazide (HCTZ). Read more about this study

Who is it for?: Ages 35 to 75 years
Conditions the study is for: Hypertension
What is being tested?: Hydrochlorothiazide (HCTZ) and Isosorbide mononitrate (ISMN)
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 64 participants
Where: No sites listed yet
Study dates: Mar 2009to Mar 2010
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 35 to 75 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Female participants must be post-menopausal
Body Mass Index (BMI) of at least 29 kg/m^2
Weight has been stable over the past 3 months
Has never been treated for hypertension or is diagnosed with hypertension taking up to 2 anti-hypertensive medications
Willing to stop hypertension treatment for 14 days prior to randomization and throughout the study
Does not have a history of diabetes

Show all 13Show fewer

In good health with the exception of hypertension
No history of abnormal heart rhythms
Part I only: willing to comply with high potassium/low sodium diet for the duration of the study
Willing to avoid strenuous physical activity during the study
Nonsmoker and/or has not used nicotine for at least 3 months and agrees to refrain from use of tobacco-containing products throughout the study
Agrees to refrain from consuming alcohol and caffeine during in-patient periods and to limit consumption at all other times during the study
Agrees not to consume grapefruit, grapefruit products, and citrus, apple, and pineapple juices 2 weeks prior to administration of the first dose of study drug

Who cannot join

History of any illness that may make their participation in the study unsafe or confuse the study results
Taking spironolactone or eplerenone
Cannot refrain from using any prescription or non-prescription drugs during the study
On a weight loss program and is not in the maintenance phase
Started a weight loss drug within 8 weeks of the first study visit
Consumes excessive amounts of alcohol or caffeine

Show all 9Show fewer

Has had major surgery, donated or lost 1 unit of blood within 4 weeks of the first study visit
History of multiple and/or severe allergies to drugs or food
Is dehydrated

About this study

Official title: A Randomized, Double-Blind, Placebo-Controlled, 2-Part Study to Evaluate the Multiple Dose Effects of Hydrochlorothiazide and Isosorbide Mononitrate on Glucose Homeostasis in Obese Patients With Hypertension

Conditions: Hypertension
Being tested: Hydrochlorothiazide (HCTZ), Comparator: Placebo to HCTZ, Isosorbide mononitrate (ISMN), Comparator: Placebo to ISMN
Medical subject headings: Hypertension

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Hydrochlorothiazide (HCTZ)Drug
Also called HCTZ
HCTZ 50 mg (two 25 mg capsules) once daily for 4 weeks per treatment period.
Comparator: Placebo to HCTZDrug
Placebo to HCTZ two 0 mg capsules once daily for 4 weeks per treatment period
Isosorbide mononitrate (ISMN)Drug
ISMN 60 mg extended release capsule once daily for 4 weeks per treatment period
Comparator: Placebo to ISMNDrug
Placebo to ISMN 0 mg capsule once daily for 4 weeks per treatment period

Study groups in NCT00871871
Study group	Role	What they receive
Part I, Placebo-HCTZ	Experimental	Placebo in Period 1 followed by HCTZ in Period 2 Receives: Drug: Hydrochlorothiazide (HCTZ); Drug: Comparator: Placebo to HCTZ
Part I, HCTZ-Placebo	Experimental	HCTZ in Period 1, followed by placebo in Period 2 Receives: Drug: Hydrochlorothiazide (HCTZ); Drug: Comparator: Placebo to HCTZ
Part II, Placebo-ISMN	Experimental	Placebo in Period 1, followed by ISMN in Period 2 Receives: Drug: Isosorbide mononitrate (ISMN); Drug: Comparator: Placebo to ISMN
Part II, ISMN-Placebo	Experimental	ISMN in Period 1, followed by placebo in Period 2 Receives: Drug: Isosorbide mononitrate (ISMN); Drug: Comparator: Placebo to ISMN

What is being measured

The primary outcome is the main question the study is designed to answer.

Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT)
Steady state was defined as 90-120 minutes post-dose. IGT was defined as a 2 hour plasma glucose >= 140 and <= 199 mg/dL during a 75g oral glucose tolerance test at screening.
Measured: 90 -120 minutes post-dose
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG)
Steady state was defined as 90-120 minutes post-dose. IFG was defined as fasting plasma glucose (FPG) between 100 and 125 mg/dL at screening.
Measured: 90 -120 minutes post-dose
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants Who Had Normal Glucose Tolerance (NGT)
Steady state was defined as 90-120 minutes post-dose. NGT participants (FPG <100 mg/dL \& 2 hour plasma glucose (PG) <140 mg/dL during a 75g oral glucose tolerance test (OGTT) at screening) were neither Impaired Glucose Tolerant (IGT) nor Impaired Fasting Glucose (IFG). IGT was defined as a 2 hour plasma glucose >= 140 and <= 199 mg/dL during a 75g oral glucose tolerance test at screening. IFG was defined as FPG between 100 and 125 mg/dL at screening.
Measured: 90 -120 minutes post-dose
Part II: Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady-state
Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes.
Measured: 90 -120 minutes post-dose

Secondary outcomes (3)

Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Glucose Tolerant (IGT)
Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes. IGT was defined as a 2 hour plasma glucose >= 140 and <= 199 mg/dL during a 75g oral glucose tolerance test at screening.
Measured: 90 -120 minutes post-dose
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Fasting Glucose (IFG)
Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes. IFG was defined as fasting plasma glucose (FPG) between 100 and 125 mg/dL at screening.
Measured: 90 -120 minutes post-dose
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Normal Glucose Tolerant (NGT)
Steady state was defined as 90-120 minutes post-dose. The ratio was the measure of the quantity of glucose disposed per unit of plasma insulin concentration (PIC). Approximate PIC was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals, time = 90, 100, 110, and 120 minutes. NGT participants (FPG <100 mg/dL \& 2 hour PG <140 mg/dL during a 75g OGTT at screening) were neither IGT nor IFG at screening. IGT - defined as a 2 hour PG >= 140 and <= 199 mg/dL during a 75g OGTT at screening. IFG - defined as FPG between 100 and 125 mg/dL at screening.
Measured: 90 -120 minutes post-dose

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Mar 2009Mar 2010

First posted30 Mar 2009 (estimated)
Study startMar 2009
Primary completionFeb 2010
Study completionMar 2010

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for HypertensionStudies of the same condition, open and under way.
More trials run by Merck Sharp & Dohme LLCThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 64 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00871871
Sponsor's protocol ID: 0000-117
Other IDs: 2009_567
Status last verified: Jul 2015
First submitted: 27 Mar 2009
Last updated: 28 Jul 2015
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

Active, not recruiting
Digital Reinforcement of Motivational Interviewing Micro-Skills Among Primary Care Healthcare Professionals
Hypertension (Without Type 2 Diabetes Mellitus)
Recruiting
Investigating Vascular Properties of HEMI and SPG Signals in Individuals With or at Risk for Chronic Kidney Disease
Chronic Kidney Disease, Hypertension (HTN)
Recruiting
Trial Phase: Syndemic Adapted Medly Uganda
Mental Health
Not yet recruitingPhase 2/3
An Open-Label Extension Study to Evaluate Inhaled Treprostinil SMI in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD)
Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease
Enrolling by invitation
Testing Implementation Strategies to Support Clinic Fidelity to an Outpatient Hypertension Bundle
Pregnancy Related, Hypertension

All Hypertension trials

Study at a glance

From the registry record, last updated by the sponsor on 28 Jul 2015. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Randomized, Double-Blind, Placebo-Controlled, 2-Part Study to Evaluate the Multiple Dose Effects of Hydrochlorothiazide and Isosorbide Mononitrate on Glucose Homeostasis in Obese Patients With Hypertension
ClinicalTrials.gov ID: NCT00871871
Acronym / sponsor ID: 0000-117
Conditions: Hypertension
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 64 participants (actual)
Lead sponsor: Merck Sharp & Dohme LLCIndustry (pharma, biotech, devices)
Study start: Mar 2009
Primary completion: Feb 2010 (actual)
Study completion: Mar 2010 (actual)
First posted: 30 Mar 2009 (estimated)
Results: Posted 22 Sep 2011

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Double blind (participant, investigator)
Number of arms: 4

Arm	Type	Receives
Part I, Placebo-HCTZ	Experimental	Drug: Hydrochlorothiazide (HCTZ), Drug: Comparator: Placebo to HCTZPlacebo in Period 1 followed by HCTZ in Period 2
Part I, HCTZ-Placebo	Experimental	Drug: Hydrochlorothiazide (HCTZ), Drug: Comparator: Placebo to HCTZHCTZ in Period 1, followed by placebo in Period 2
Part II, Placebo-ISMN	Experimental	Drug: Isosorbide mononitrate (ISMN), Drug: Comparator: Placebo to ISMNPlacebo in Period 1, followed by ISMN in Period 2
Part II, ISMN-Placebo	Experimental	Drug: Isosorbide mononitrate (ISMN), Drug: Comparator: Placebo to ISMNISMN in Period 1, followed by placebo in Period 2

Who may qualify

Ages: 35 to 75 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (13 listed)

Female participants must be post-menopausal
Body Mass Index (BMI) of at least 29 kg/m^2
Weight has been stable over the past 3 months
Has never been treated for hypertension or is diagnosed with hypertension taking up to 2 anti-hypertensive medications
Willing to stop hypertension treatment for 14 days prior to randomization and throughout the study

Key exclusion criteria (9 listed)

History of any illness that may make their participation in the study unsafe or confuse the study results
Taking spironolactone or eplerenone
Cannot refrain from using any prescription or non-prescription drugs during the study
On a weight loss program and is not in the maintenance phase
Started a weight loss drug within 8 weeks of the first study visit

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Hydrochlorothiazide (HCTZ)Also: HCTZHCTZ 50 mg (two 25 mg capsules) once daily for 4 weeks per treatment period.	Drug	Part I, HCTZ-Placebo, Part I, Placebo-HCTZ
Comparator: Placebo to HCTZPlacebo to HCTZ two 0 mg capsules once daily for 4 weeks per treatment period	Drug	Part I, HCTZ-Placebo, Part I, Placebo-HCTZ
Isosorbide mononitrate (ISMN)ISMN 60 mg extended release capsule once daily for 4 weeks per treatment period	Drug	Part II, ISMN-Placebo, Part II, Placebo-ISMN
Comparator: Placebo to ISMNPlacebo to ISMN 0 mg capsule once daily for 4 weeks per treatment period	Drug	Part II, ISMN-Placebo, Part II, Placebo-ISMN

Primary outcome

Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT)
Time frame: 90 -120 minutes post-dose
Steady state was defined as 90-120 minutes post-dose. IGT was defined as a 2 hour plasma glucose >= 140 and <= 199 mg/dL during a 75g oral glucose tolerance test at screening.
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG)
Time frame: 90 -120 minutes post-dose
Steady state was defined as 90-120 minutes post-dose. IFG was defined as fasting plasma glucose (FPG) between 100 and 125 mg/dL at screening.
Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants Who Had Normal Glucose Tolerance (NGT)
Time frame: 90 -120 minutes post-dose
Steady state was defined as 90-120 minutes post-dose. NGT participants (FPG <100 mg/dL \& 2 hour plasma glucose (PG) <140 mg/dL during a 75g oral glucose tolerance test (OGTT) at screening) were neither Impaired Glucose Tolerant (IGT) nor Impaired Fasting Glucose (IFG). IGT was defined as a 2 hour plasma glucose >= 140 and <= 199 mg/dL during a 75g oral glucose tolerance test at screening. IFG was defined as FPG between 100 and 125 mg/dL at screening.
Part II: Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady-state
Time frame: 90 -120 minutes post-dose
Steady state was defined as 90-120 minutes post-dose. The ratio was the quantity of glucose disposed by the body per kg body weight per minute at steady state divided by the approximate steady state plasma insulin concentration. The approximate steady state plasma insulin concentration was estimated by the time-weighted average of the insulin concentration measured at 10 minute intervals in which time = 90, 100, 110, and 120 minutes.

3 secondary outcomes

Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Glucose Tolerant (IGT)
Time frame: 90 -120 minutes post-dose
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Impaired Fasting Glucose (IFG)
Time frame: 90 -120 minutes post-dose
Part I: Change in the Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady State in Participants With Normal Glucose Tolerant (NGT)
Time frame: 90 -120 minutes post-dose

Results and safety

Results posted to the registry on 22 Sep 2011, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
HCTZ First, Then HCTZ Placebo	18	15
HCTZ Placebo First, Then HCTZ	18	15
ISMN First, Then ISMN Placebo	0	0
ISMN Placebo First, Then ISMN	0	0

Primary outcome: Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT)

Time frame: 90 -120 minutes post-dose. Least squares mean (Standard Deviation). Unit: ng/minute

Measure	Hydrochlorothiazide (HCTZ) n = 5	Hydrochlorothiazide (HCTZ) Placebo n = 5
Value	3.44 (1.03)	3.55 (1.03)

Hydrochlorothiazide (HCTZ) vs Hydrochlorothiazide (HCTZ) Placebo: Least squares mean difference: -0.10 (90% CI -0.22 to 0.01), p = 0.067, ANCOVA

Population analysed: Number of participants with IGT.

Primary outcome: Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Fasting Glucose (IFG)

Time frame: 90 -120 minutes post-dose. Least squares mean (Standard Deviation). Unit: ng/minute

Measure	Hydrochlorothiazide (HCTZ) n = 7	Hydrochlorothiazide (HCTZ) Placebo n = 8
Value	5.60 (1.45)	4.50 (0.95)

Hydrochlorothiazide (HCTZ) vs Hydrochlorothiazide (HCTZ) Placebo: Least squares mean difference: 1.10 (90% CI 0.86 to 1.34), p >0.500, ANCOVA

Population analysed: Number of participants with IFG.

Primary outcome: Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants Who Had Normal Glucose Tolerance (NGT)

Time frame: 90 -120 minutes post-dose. Least squares mean (Standard Deviation). Unit: ng/minute

Measure	Hydrochlorothiazide (HCTZ) n = 22	Hydrochlorothiazide (HCTZ) Placebo n = 23
Value	5.54 (2.15)	5.01 (1.63)

Hydrochlorothiazide (HCTZ) vs Hydrochlorothiazide (HCTZ) Placebo: Least squares mean difference: 0.54 (90% CI 0.40 to 0.67), p >0.500, ANCOVA

Population analysed: Number of participants with NGT.

Primary outcome: Part II: Ratio of Whole Body Glucose Disposal to Plasma Insulin at Steady-state

Time frame: 90 -120 minutes post-dose. Least squares mean (Standard Deviation). Unit: (mg/kg/minute)/(µIU/mL)

Measure	Isosorbide Mononitrate (ISMN) n = 20	Isosorbide Mononitrate (ISMN) Placebo n = 23
Value	0.040 (0.027)	0.044 (0.041)

Isosorbide Mononitrate (ISMN) vs Isosorbide Mononitrate (ISMN) Placebo: Least squares mean difference: 0.004 (90% CI -0.023 to 0.014), p = 0.342, ANOVA

Population analysed: Number of participants who took ISMN/placebo.

3 secondary outcomes are reported in the full results.

Adverse events

Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
HCTZ	0 of 36 (0%)	29 of 36 (80.6%)	Not reported
HCTZ Placebo	0 of 36 (0%)	25 of 36 (69.4%)	Not reported
ISMN	0 of 28 (0%)	26 of 28 (92.9%)	Not reported
ISMN Placebo	0 of 28 (0%)	17 of 28 (60.7%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 28 Jul 2015.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.

Related trials for Hypertension

Active, not recruiting
Digital Reinforcement of Motivational Interviewing Micro-Skills Among Primary Care Healthcare Professionals
Hypertension (Without Type 2 Diabetes Mellitus)
Recruiting
Investigating Vascular Properties of HEMI and SPG Signals in Individuals With or at Risk for Chronic Kidney Disease
Chronic Kidney Disease, Hypertension (HTN)
Recruiting
Trial Phase: Syndemic Adapted Medly Uganda
Mental Health
Not yet recruitingPhase 2/3
An Open-Label Extension Study to Evaluate Inhaled Treprostinil SMI in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD)
Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease
Enrolling by invitation
Testing Implementation Strategies to Support Clinic Fidelity to an Outpatient Hypertension Bundle
Pregnancy Related, Hypertension

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Medical Monitor study director

Merck Sharp & Dohme LLC

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Hydrochlorothiazide (HCTZ) and Isosorbide mononitrate (ISMN) in people with Hypertension, run by Merck Sharp & Dohme LLC.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Jul 2015. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Sep 2011). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Part I: Change in Insulin Secretion at Steady-state Compared to Placebo in Participants With Impaired Glucose Tolerance (IGT) (time frame: 90 -120 minutes post-dose). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00871871.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jul 2015.