OverweightNCT02333461
Evaluation of Botanicals for Mechanisms Related to Appetite and Fat Metabolism
A study testing Apple, Grape and Raspberry in people with Overweight and Obesity, run by Access Business Group.
Trial summary
Excess caloric consumption, particularly from inexpensive, energy dense foods that are high in fat and refined carbohydrates, is a major driver of the global obesity epidemic. Dietary supplements that promote reduced intake of energy dense foods and/or impact the absorption and metabolism of fat and carbohydrates in… Read more about this study
- Who is it for?
- Ages 18 to 70 yearsHealthy volunteers can take part
- Conditions the study is for
- Overweight, Obesity
- What is being tested?
- Apple, Grape and Raspberry
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 90 participants
- Where
- No sites listed yet
- Study dates
- May 2012to Aug 2012
- Phase
- Interventional
- Are there results?
- None posted in the registry
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 18 to 70 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Overweight/obese (BMI of 25-35 kg/m2) men and women.
- Participant must be 18-70 years of age.
- Considered healthy with no evidence of chronic diseases.
- Willing to maintain a consistent diet and exercise pattern throughout the duration of the study.
- Willing to consume a dairy and egg-based fat challenge meal twice, at start and end of study (V2 \& V3).
Who cannot join
- History of allergic reaction to fruit, dairy or egg products.
- Current smoker or history of tobacco use within the past year.
- Use of dietary supplements within 1 week prior to Visit 2 and unwilling to refrain from use through the duration of the trial. Supplements include any vitamins, minerals, and herbal products, including herbal drinks.
- Use of fish oil supplements within the past 8 weeks.
- Consumption of fatty fish one or more times per week within the past 8 weeks (e.g., mackerel, salmon, trout, canned albacore tuna, sardines, haddock, cod, hake, halibut, shrimp, sole, flounder, perch, black bass, swordfish, oysters, Alaskan king crab).
- Presence of cardiovascular disease, cancer, diabetes mellitus, inflammatory bowel disease, lactose intolerance, or any other chronic health condition identified from the findings of the interview.
Show all 19Show fewer
- History of gastric bypass or other surgery that physically alters the gastrointestinal tract.
- Blood pressure greater > 140 mm Hg systolic or > 90 mm Hg diastolic during seated, resting measurement on two consecutive occasions during visit 1.
- Fasting serum triglycerides > 200 mg/dl.
- Use of lipid lowering medications or dietary supplements.
- Use of blood pressure lowering medications or dietary supplements.
- Use of Coumadin, aspirin, or other medications that influence hemostasis.
- Daily use of low dose (< 81 mg) aspirin is allowed.
- Use of antibiotics within the past week.
- Chronic or therapeutic use of antacids, H2 agonists, and proton pump inhibitors.
- Use of selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and/or any other drug with vasoconstricting properties.
- Pregnant or lactating women, or women of child-bearing potential unwilling to use a medically approved form of birth control.
- History, in the past year, of current abuse of drugs or alcohol, or intake > 14 alcoholic beverages per week.
- Participation in another clinical trial within 28 days of enrollment into the study.
About this study
Official title: Study to Evaluate Botanicals for Mechanisms Related to Appetite and Fat Metabolism in Healthy, Overweight and Obese Individuals
Excess caloric consumption, particularly from inexpensive, energy dense foods that are high in fat and refined carbohydrates, is a major driver of the global obesity epidemic. Dietary supplements that promote reduced intake of energy dense foods and/or impact the absorption and metabolism of fat and carbohydrates in the body can be used to help consumers control their weight. We identified two separate mechanistic approaches to target these effects.
Diacylglycerol acyltransferase-1 (DGAT-1) is an enzyme involved in the formation of dietary fat into circulating triglycerides within the body. Once dietary fat is digested and absorbed, the resulting fatty acids are re-esterified into triglycerides. Inhibition of DGAT-1 results in delayed and decreased re-esterification of dietary fats into circulating triglycerides. It is hypothesized that this effect may lead to decreased deposition of excess dietary fat as adipose tissue, possibly due to increased fatty acid oxidation in the enterocytes.
Read more
Ghrelin is a hormone that is known to stimulate appetite in humans. When calorie dense fatty foods are sensed in the stomach, ghrelin is acylated and activated via ghrelin O-acyltransferase (GOAT). The activation step attaches a medium chain fatty acid to the ghrelin molecule that enables it to transmit a signal in the brain that triggers eating and fat storage in adipose tissue. Interfering with the GOAT pathway will inhibit ghrelin activation and possibly diminish food intake and lipid storage. This concept is supported by animal studies in which weight gain in a high fat diet model is prevented when GOAT is inhibited.
Our objective was to determine whether botanicals demonstrating in vitro DGAT-1 and GOAT inhibition have similar mechanistic effects in the human body. Based on the results of this study, prototype formulas may be developed and clinically- tested for outcomes related to weight management.
Read the detailed description
Excess caloric consumption, particularly from inexpensive, energy dense foods that are high in fat and refined carbohydrates, is a major driver of the global obesity epidemic. Dietary supplements that promote reduced intake of energy dense foods and/or impact the absorption and metabolism of fat and carbohydrates in the body can be used to help consumers control their weight. We identified two separate mechanistic approaches to target these effects.
Diacylglycerol acyltransferase-1 (DGAT-1) is an enzyme involved in the formation of dietary fat into circulating triglycerides within the body. Once dietary fat is digested and absorbed, the resulting fatty acids are re-esterified into triglycerides. Inhibition of DGAT-1 results in delayed and decreased re-esterification of dietary fats into circulating triglycerides. It is hypothesized that this effect may lead to decreased deposition of excess dietary fat as adipose tissue, possibly due to increased fatty acid oxidation in the enterocytes.
Ghrelin is a hormone that is known to stimulate appetite in humans. When calorie dense fatty foods are sensed in the stomach, ghrelin is acylated and activated via ghrelin O-acyltransferase (GOAT). The activation step attaches a medium chain fatty acid to the ghrelin molecule that enables it to transmit a signal in the brain that triggers eating and fat storage in adipose tissue. Interfering with the GOAT pathway will inhibit ghrelin activation and possibly diminish food intake and lipid storage. This concept is supported by animal studies in which weight gain in a high fat diet model is prevented when GOAT is inhibited.
Ghrelin levels are positively associated with stress, sleep deprivation, and caloric restriction. Weight loss induced by exercise does not have the same positive association with ghrelin levels that caloric restriction alone has. Ghrelin levels are influenced by diet composition, however, the results vary considerably between trials.
Over 160 botanical extracts from our internal ingredient library were screened at a single concentration for inhibition of both DGAT-1 and GOAT. Botanicals that were identified as having at least 75% activity were then titrated to identify those with IC50 values < 25 g/ml or less. We narrowed our list of viable ingredients by looking at those with activity in both the DGAT-1 and GOAT in vitro enzyme bioassay models. The top performing botanicals were then evaluated in a cellular model for DGAT-1 inhibition. Those with the highest inhibition activity in this model were considered lead candidates. A preliminary literature search was conducted and the final filter included factors such as cost and regulatory acceptability which results in the four ingredients being tested in the current clinical protocol.Our objective was to determine whether these four ingredients have similar mechanistic effects in the human body.
- Conditions
- Overweight, Obesity
- Being tested
- Placebo, Apple, Grape, Raspberry, Apricot/Nectarine
- Medical subject headings
- Overweight, Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboDietary supplement
Participants were randomly assigned to receive one of four botanical interventions or placebo.
AppleDietary supplement
Participants were randomly assigned to receive one of four botanical interventions or placebo.
GrapeDietary supplement
Participants were randomly assigned to receive one of four botanical interventions or placebo.
RaspberryDietary supplement
Participants were randomly assigned to receive one of four botanical interventions or placebo.
Apricot/NectarineDietary supplement
Participants were randomly assigned to receive one of four botanical interventions or placebo.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | 333 mg capsule comprised of silicified microcrystalline cellulose, magnesium stearate, modified cellulose gum, silicon dioxide, dextrose, corn starch, and caramel color. Consumed as six capsules once daily (total of 2 g/day) with the morning meal for a period of seven days. Receives: Dietary Supplement: Placebo |
| Apple | Experimental | 333 mg capsule comprised of apple peel extract (115:1, standardized to 80% polyphenol and 5% phlorizin). Consumed as six capsules once daily (total of 2 g/day) with the morning meal for a period of seven days. Receives: Dietary Supplement: Apple |
| Grape | Experimental | 333 mg capsule comprised of grape extract (8000:1, standardized to 75% total polyphenol, 50% oligomeric proanthocyanidin). Consumed as six capsules once daily (total of 2 g/day) with the morning meal for a period of seven days. Receives: Dietary Supplement: Grape |
| Red Raspberry | Experimental | 333 mg capsule comprised of red raspberry leaf extract (4:1, standardized to 6% ellagic acid). Consumed as six capsules once daily (total of 2 g/day) with the morning meal for a period of seven days. Receives: Dietary Supplement: Raspberry |
| Apricot/Nectarine | Experimental | 333 mg capsule comprised of apricot/nectarine extract (40:1, standardized to 50% polyphenol). Receives: Dietary Supplement: Apricot/Nectarine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Serum triglyceride response (area under the curve = AUC) following consumption of a standardized high fat meal challenge.
Measured: Six hours
Plasma acylated ghrelin response (AUC) following consumption of a standardized high fat meal challenge
Measured: Three hours
Secondary outcomes (4)
Maximum concentration (Cmax) for serum triglycerides following consumption of a standardized high fat meal challenge
Measured: Six hours
Time to maximum concentration (Tmax) for serum triglycerides following consumption of a standardized high fat meal challenge
Measured: Six hours
Cmax for plasma acylated ghrelin following consumption of a standardized high fat meal challenge
Measured: Three hours
Tmax for plasma acylated ghrelin following consumption of a standardized high fat meal challenge
Measured: Three hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jan 2015 (estimated)
- Study startMay 2012
- Primary completionAug 2012
- Study completionAug 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for OverweightStudies of the same condition, open and under way.
- 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 N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 90 participants (actual)
Sponsor and investigators
- Lead sponsor
- Access Business Group
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Radiant Research
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02333461
- Sponsor's protocol ID
- BURN CURB POM-1
- Status last verified
- Jan 2015
- First submitted
- 6 Jan 2015
- Last updated
- 7 Jan 2015
- Results posted
- No
- Data monitoring committee
- No
Publications
Velliquette RA, Grann K, Missler SR, Patterson J, Hu C, Gellenbeck KW, Scholten JD, Randolph RK. Identification of a botanical inhibitor of intestinal diacylglyceride acyltransferase 1 activity via in vitro screening and a parallel, randomized, blinded, placebo-controlled clinical trial. Nutr Metab (Lond). 2015 Aug 6;12:27. doi: 10.1186/s12986-015-0025-2. eCollection 2015.
PubMed 26246845
Study at a glance
From the registry record, last updated by the sponsor on 7 Jan 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Study to Evaluate Botanicals for Mechanisms Related to Appetite and Fat Metabolism in Healthy, Overweight and Obese Individuals
- ClinicalTrials.gov ID
- NCT02333461
- Acronym / sponsor ID
- BURN CURB POM-1
- Conditions
- Overweight, Obesity
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 90 participants (actual)
- Lead sponsor
- Access Business GroupIndustry (pharma, biotech, devices)
- Collaborators
- Radiant Research
- Study start
- May 2012
- Primary completion
- Aug 2012 (actual)
- Study completion
- Aug 2012 (actual)
- First posted
- 7 Jan 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Excess caloric consumption, particularly from inexpensive, energy dense foods that are high in fat and refined carbohydrates, is a major driver of the global obesity epidemic. Dietary supplements that promote reduced intake of energy dense foods and/or impact the absorption and metabolism of fat and carbohydrates in the body can be used to help consumers control their weight. We identified two separate mechanistic approaches to target these effects.
Diacylglycerol acyltransferase-1 (DGAT-1) is an enzyme involved in the formation of dietary fat into circulating triglycerides within the body. Once dietary fat is digested and absorbed, the resulting fatty acids are re-esterified into triglycerides. Inhibition of DGAT-1 results in delayed and decreased re-esterification of dietary fats into circulating triglycerides. It is hypothesized that this effect may lead to decreased deposition of excess dietary fat as adipose tissue, possibly due to increased fatty acid oxidation in the enterocytes.
Ghrelin is a hormone that is known to stimulate appetite in humans. When calorie dense fatty foods are sensed in the stomach, ghrelin is acylated and activated via ghrelin O-acyltransferase (GOAT). The activation step attaches a medium chain fatty acid to the ghrelin molecule that enables it to transmit a signal in the brain that triggers eating and fat storage in adipose tissue. Interfering with the GOAT pathway will inhibit ghrelin activation and possibly diminish food intake and lipid storage. This concept is supported by animal studies in which weight gain in a high fat diet model is prevented when GOAT is inhibited.
Our objective was to determine whether botanicals demonstrating in vitro DGAT-1 and GOAT inhibition have similar mechanistic effects in the human body. Based on the results of this study, prototype formulas may be developed and clinically- tested for outcomes related to weight management.
Detailed description
Excess caloric consumption, particularly from inexpensive, energy dense foods that are high in fat and refined carbohydrates, is a major driver of the global obesity epidemic. Dietary supplements that promote reduced intake of energy dense foods and/or impact the absorption and metabolism of fat and carbohydrates in the body can be used to help consumers control their weight. We identified two separate mechanistic approaches to target these effects.
Diacylglycerol acyltransferase-1 (DGAT-1) is an enzyme involved in the formation of dietary fat into circulating triglycerides within the body. Once dietary fat is digested and absorbed, the resulting fatty acids are re-esterified into triglycerides. Inhibition of DGAT-1 results in delayed and decreased re-esterification of dietary fats into circulating triglycerides. It is hypothesized that this effect may lead to decreased deposition of excess dietary fat as adipose tissue, possibly due to increased fatty acid oxidation in the enterocytes.
Ghrelin is a hormone that is known to stimulate appetite in humans. When calorie dense fatty foods are sensed in the stomach, ghrelin is acylated and activated via ghrelin O-acyltransferase (GOAT). The activation step attaches a medium chain fatty acid to the ghrelin molecule that enables it to transmit a signal in the brain that triggers eating and fat storage in adipose tissue. Interfering with the GOAT pathway will inhibit ghrelin activation and possibly diminish food intake and lipid storage. This concept is supported by animal studies in which weight gain in a high fat diet model is prevented when GOAT is inhibited.
Ghrelin levels are positively associated with stress, sleep deprivation, and caloric restriction. Weight loss induced by exercise does not have the same positive association with ghrelin levels that caloric restriction alone has. Ghrelin levels are influenced by diet composition, however, the results vary considerably between trials.
Over 160 botanical extracts from our internal ingredient library were screened at a single concentration for inhibition of both DGAT-1 and GOAT. Botanicals that were identified as having at least 75% activity were then titrated to identify those with IC50 values < 25 g/ml or less. We narrowed our list of viable ingredients by looking at those with activity in both the DGAT-1 and GOAT in vitro enzyme bioassay models. The top performing botanicals were then evaluated in a cellular model for DGAT-1 inhibition. Those with the highest inhibition activity in this model were considered lead candidates. A preliminary literature search was conducted and the final filter included factors such as cost and regulatory acceptability which results in the four ingredients being tested in the current clinical protocol.Our objective was to determine whether these four ingredients have similar mechanistic effects in the human body.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Dietary Supplement: Placebo333 mg capsule comprised of silicified microcrystalline cellulose, magnesium stearate, modified cellulose gum, silicon dioxide, dextrose, corn starch, and caramel color. Consumed as six capsules once daily (total of 2 g/day) with the morning meal for a period of seven days. |
| Apple | Experimental | Dietary Supplement: Apple333 mg capsule comprised of apple peel extract (115:1, standardized to 80% polyphenol and 5% phlorizin). Consumed as six capsules once daily (total of 2 g/day) with the morning meal for a period of seven days. |
| Grape | Experimental | Dietary Supplement: Grape333 mg capsule comprised of grape extract (8000:1, standardized to 75% total polyphenol, 50% oligomeric proanthocyanidin). Consumed as six capsules once daily (total of 2 g/day) with the morning meal for a period of seven days. |
| Red Raspberry | Experimental | Dietary Supplement: Raspberry333 mg capsule comprised of red raspberry leaf extract (4:1, standardized to 6% ellagic acid). Consumed as six capsules once daily (total of 2 g/day) with the morning meal for a period of seven days. |
| Apricot/Nectarine | Experimental | Dietary Supplement: Apricot/Nectarine333 mg capsule comprised of apricot/nectarine extract (40:1, standardized to 50% polyphenol). |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Overweight/obese (BMI of 25-35 kg/m2) men and women.
- Participant must be 18-70 years of age.
- Considered healthy with no evidence of chronic diseases.
- Willing to maintain a consistent diet and exercise pattern throughout the duration of the study.
- Willing to consume a dairy and egg-based fat challenge meal twice, at start and end of study (V2 \& V3).
Key exclusion criteria (19 listed)
- History of allergic reaction to fruit, dairy or egg products.
- Current smoker or history of tobacco use within the past year.
- Use of dietary supplements within 1 week prior to Visit 2 and unwilling to refrain from use through the duration of the trial. Supplements include any vitamins, minerals, and herbal products, including herbal drinks.
- Use of fish oil supplements within the past 8 weeks.
- Consumption of fatty fish one or more times per week within the past 8 weeks (e.g., mackerel, salmon, trout, canned albacore tuna, sardines, haddock, cod, hake, halibut, shrimp, sole, flounder, perch, black bass, swordfish, oysters, Alaskan king crab).
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 |
|---|---|---|
| PlaceboParticipants were randomly assigned to receive one of four botanical interventions or placebo. | Dietary supplement | Placebo |
| AppleParticipants were randomly assigned to receive one of four botanical interventions or placebo. | Dietary supplement | Apple |
| GrapeParticipants were randomly assigned to receive one of four botanical interventions or placebo. | Dietary supplement | Grape |
| RaspberryParticipants were randomly assigned to receive one of four botanical interventions or placebo. | Dietary supplement | Red Raspberry |
| Apricot/NectarineParticipants were randomly assigned to receive one of four botanical interventions or placebo. | Dietary supplement | Apricot/Nectarine |
Primary outcome
Serum triglyceride response (area under the curve = AUC) following consumption of a standardized high fat meal challenge.
Time frame: Six hours
Plasma acylated ghrelin response (AUC) following consumption of a standardized high fat meal challenge
Time frame: Three hours
4 secondary outcomes
Maximum concentration (Cmax) for serum triglycerides following consumption of a standardized high fat meal challenge
Time frame: Six hours
Time to maximum concentration (Tmax) for serum triglycerides following consumption of a standardized high fat meal challenge
Time frame: Six hours
Cmax for plasma acylated ghrelin following consumption of a standardized high fat meal challenge
Time frame: Three hours
Tmax for plasma acylated ghrelin following consumption of a standardized high fat meal challenge
Time frame: Three hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Jan 2015.
- Derived from this study: PubMed 26246845Velliquette RA, Grann K, Missler SR, Patterson J, Hu C, Gellenbeck KW, Scholten JD, Randolph RK. Identification of a botanical inhibitor of intestinal diacylglyceride acyltransferase 1 activity via in vitro screening and a parallel, randomized, blinded, placebo-controlled clinical trial. Nutr Metab (Lond). 2015 Aug 6;12:27. doi: 10.1186/s12986-015-0025-2. eCollection 2015.
Related trials for Overweight
RecruitingObservational study
Endoscopic Sleeve Gastroplasty (ESG) Prospective Trial for Obesity (EGO-Trial)
Obesity
Active, not recruitingPhase 4
Effects of Sequential Therapy With Mexidol® (Intravenous) and Mexidol® FORTE 250 (Oral) on Functional Brain Activity Assessed by Functional Magnetic Resonance Imaging and Biochemical Parameters in Patients With Chronic Cerebral Ischemia: A Comparison of Patients With and Without Metabolic Disorders
Metabolic Abnormalities, Obesity & Overweight
Recruiting
Exercise Training and Vitamin D Metabolism
Obesity & Overweight, Vitamin D
Recruiting
Metabolic Health, Bones and Nuts During Weight Loss in Adults
Weight Loss, Bone Density
Active, not recruiting
Effect of Probiotics on Insulin Sensitivity in Overweight and Obese Pregnancy
Obesity & Overweight, Gestational Diabetes Mellitus (GDM)
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.
The record lists no contact. Use the official record to reach the sponsor.
Questions about this trial
What is this clinical trial studying?
A study testing Apple, Grape and Raspberry in people with Overweight and Obesity, run by Access Business Group.
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 5 inclusion and 19 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 7 Jan 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Serum triglyceride response (area under the curve = AUC) following consumption of a standardized high fat meal challenge. (time frame: Six hours). The study lists 2 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 NCT02333461, which also lists 1 linked publication.
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 7 Jan 2015.