Dietary ModificationPhase 1/2LBPNCT02701959
Effect of Lettuce With Different Nitrate Contents on Blood Pressure
A Phase 1/2 study testing High Nitrate Lettuce and Low Nitrate Lettuce in people with Dietary Modification and Blood Pressure, run by Newcastle University at 1 site in United Kingdom.
Trial summary
Leafy vegetables are a natural source of dietary nitrate, which may reduce systolic blood pressure (BP). However, the evidence has been obtained from studies using nitrate solutions (i.e., potassium or sodium nitrate) or beetroot juice supplementation which have a suitable placebo for the design of double-blind… Read more about this study
- Who is it for?
- Ages 18 to 35 yearsHealthy volunteers can take part
- Conditions the study is for
- Dietary Modification, Blood Pressure
- What is being tested?
- High Nitrate Lettuce and Low Nitrate Lettuce
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Apr 2015to Aug 2015
- Phase
- Phase 1/2
- 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 35 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- The investigators aim to recruit 20 healthy young volunteers, non-smoking, male and female aged 18-35 years with a body mass index (BMI) in the range of 20 to 25 kg/m2.
Who cannot join
- Current participation in other clinical investigations.
- Mouthwash users.
- Vegetarianism (likely to have very high nitrate intake)
- Dislike to lettuce consumption or inability to comply with the study diet (lack of compliance)
- Use of antihypertensive or cholesterol lowering medication.
- History of any major illness such as cancer; or cholesterol lowering medication; history of cardiovascular or peripheral vascular disease;
Show all 12Show fewer
- History of any major illness such as cancer; a psychiatric illness; recent history of asthma, renal, liver or gastrointestinal disease.
- Use of antibiotics within previous 2 months; current or recent (within previous 6 months) significant weight loss or gain (>6% of body weight); --woman who were pregnant, lactating or wishing to become pregnant during the study.
- Previous diagnosis of type 1 or type-2 diabetes treated with insulin (modification of regulation of intermediate metabolism).
- Major surgical operations interfering with the study outcomes (systemic effects on study outcomes).
- Alcohol intake >21 units/week for men and >14 units/week women
- Non English speakers or volunteers requiring translators or interpreters (since these services are not available for this study).
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
School of Agriculture, Food and Rural Development
Newcastle upon Tyne, England, NE1
About this study
Official title: Growth of Lettuce With Different Content of Inorganic Nitrate as a Feeding Strategy for Placebo-controlled Nutritional Interventions to Test the Effects of Inorganic Nitrate on Human Health
Leafy vegetables are a natural source of dietary nitrate, which may reduce systolic blood pressure (BP). However, the evidence has been obtained from studies using nitrate solutions (i.e., potassium or sodium nitrate) or beetroot juice supplementation which have a suitable placebo for the design of double-blind clinical trials. However, the design of food-based nutritional interventions is complicated by the fact that an appropriate placebo treatment is not available and, therefore, it is not possible to meet the criteria for proper double-blind randomised placebo-controlled intervention trials. In addition, the biological effects of processed products such as beetroot juice or solutions with a pharmacological grade may be different from that of fresh vegetables, e.g. due to conversion of nitrate to nitrite in the mouth during chewing.
Objectives: to investigate whether two sets of lettuce specifically grown with different nitrate content but otherwise similar composition show different effects on nitrate uptake and bioavailability in humans. Additionally, the investigators also aim to design human intervention studies to investigate the effect of intake of lettuce with different nitrate content on vascular health.
These objectives will be tested by growing lettuce with different fertiliser compositions resulting in high and low nitrate content and then investigating the bioavailability and short-term effect on BP in healthy young volunteers in a double-blind cross-over design. Eligible subjects will consume one meal each of either low or high nitrate lettuce. Urine, blood and saliva samples will be collected at baseline, for 6 hours after the ingestion and then again after 24hr. Blood Pressure BP will be measured continuously for 24 hours starting at baseline. The volunteers will repeat the intervention with the second treatment.
Read the detailed description
Study Design and Subjects: This study is designed as a double-blind, randomized, crossover, intervention trial in which thirty healthy young volunteers (BMI: 20-25 kg/m2), non-smoking subjects (age: 18-35 years) will be recruited. In each of two intervention periods, subjects will be asked to eat 50g of either high nitrate lettuce or low nitrate lettuce (placebo) on a single occasion (the second visit) with dietary restriction for 3 days prior to the second visit and in the 24 hr period following after the consumption, concluded with a third visit, with at least 3 weeks washout period before the second 2-day intervention period. Urine, saliva and blood samples will be collected during a 6-hour period during the second visit. Urine samples will be collected during 24h from consumption until the third visit, to assess the pharmacokinetics and bioavailability and compliance to the interventions (details in the diagram of human trial).
The primary outcomes are 24-hour BP and nitrate content in urine, plasma and saliva. Samples will be collected into tubes and then analysed in the laboratory for the nitrate content (NO3-) by gas chromatography-mass spectroscopy (GCMS). Participants will follow specific dietary and lifestyle instructions to minimise confounding effects.
Participant will receive a small honorarium after the study and reasonable travel expenses will be reimbursed.
Dietary Interventions: Participants will be asked to arrive fasting in the morning of the second (main) visit and will consume a standard meal (Chicken Hotpot from ASDA) with the same drink water at the evening before and the evening after the visit, as well as following a diet that excludes a list of specific foods containing high nitrate (rocket, spinach, other leafy vegetables, radish and beet root), cured meat, cured seafood and cured fish, mature cheese for 24hr prior to the study and fasting on the morning of the study.
Anthropometry: This includes the measurements of body weight, height and waist circumference according to standardised protocols. Procedures are safe, not invasive and induce minimal discomfort for the participants.
Body Composition: This includes the measurement of body fat and muscle using a non-invasive technique called bio impedance analysis using a leg-to-leg bioelectrical impedance device (TANITA 300 MA). The procedure is safe, non-invasive and induces minimal discomfort for the participant. The duration of the measurement is of approximately 3-5 minutes.
24-hr BP monitoring: participants will be fitted with an automated portable device to measure BP over a 24-hr period. Participants will be instructed on how to safely operate the device. The measurement are safe and minimally invasive. BP readings will be recorded every 30 minutes during day time and every hour during the night to minimise the potential impact on sleep quality.
Urine samples: The first morning void (FMV) will be collected at home (pre supplementation) and after arrival full urine samples (all that the volunteer is able to produce) at set times before and after the supplementation (between baseline and 6hr) at NU-Food research facility. Subsequent collections afterwards (between 6-12hr and 12-24 hr) will take place at home in appropriate plastic containers and the samples will be collected at the final visit 24hr after the consumption. After measuring the volume of each sample, sub samples will be stored for analysis and for calculation of pharmacokinetics.
Saliva samples: a small saliva sample (~2ml) will be collected in disposable plastic containers at baseline and at every hour for 6 hours at NU-Food research facility; and then after 9 and 12 hour at home, with the final sample taken after 24 hr.
Blood Samples: Venous blood samples (LH 6 ml) will be collected at baseline, three and six hours post supplementation of treatments and then again after 24 hr.
- Conditions
- Dietary Modification, Blood Pressure
- Being tested
- High Nitrate Lettuce, Low Nitrate Lettuce
- Keywords
- Nitric oxide, Dietary intervention trail
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
High Nitrate LettuceDietary supplement
The lettuce has been grown with high concentration of nitrogen fertilizer (150ppm) to produce the high of nitrate content in the lettuce, the nitrate content of 50 grams of high nitrate lettuce was (~530 mg nitrate derived).
Low Nitrate LettuceDietary supplement
The lettuce has been grown with low concentration of nitrogen fertilizer (25ppm) to produce the low amount of nitrate in the lettuce, the nitrate content of 50 grams of high nitrate lettuce was (~3 mg nitrate derived).
| Study group | Role | What they receive |
|---|---|---|
| Low nitrate lettuce | Placebo comparator | 50g of low nitrate lettuce (placebo) on single occasions Receives: Dietary Supplement: Low Nitrate Lettuce |
| High nitrate lettuce | Active comparator | 50g of high nitrate lettuce (intervention) on single occasions Receives: Dietary Supplement: High Nitrate Lettuce |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in 24-hour Ambulatory Blood Pressure (AMBP)
Change in Systolic and Diastolic Blood Pressure at baseline and every 30 minutes at day time and every hour at night time for 24 hours.
Measured: Baseline and 24 hours
Secondary outcomes (5)
Change in bio-availability of nitrate and nitrite in plasma
Change in plasma nitrate and nitrite at baseline, 3 hours, 6 hours and 24 hours from intervention.
Measured: 24 hours
Change in Cyclic Guanosine Monophosphate (cGMP) in plasma samples
Change in Cyclic Guanosine Monophosphate (cGMP) in plasma samples at baseline, 3 hours, 6 hours and 24 hours from intervention.
Measured: 24 hours
Change in bio-availability of nitrate and nitrite in urine samples
Change in urinary nitrate and nitrite at baseline, 0-3, 3-6, 6-12 and 12-24 hours from intervention.
Measured: 24 hours
Change in bio-availability of nitrate and nitrite in saliva samples
Change in salivary nitrate and nitrite at baseline, 0, 1, 2, 3, 4, 5, 6, 9, 12 and 24 hours from intervention.
Measured: 24 hours
Change in Antioxidant capacity of Ferric Reducing Antioxidant Power (FRAP) and Trolox Equivalent Antioxidant Capacity (TEAC) in plasma samples.
Change in Antioxidant capacity of Ferric Reducing Antioxidant Power (FRAP) and Trolox Equivalent Antioxidant Capacity (TEAC) in plasma samples at baseline, 3 hours, 6 hours and 24 hours from intervention.
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Mar 2016 (estimated)
- Study startApr 2015
- Primary completionAug 2015
- Study completionAug 2015
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 Dietary ModificationStudies 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 1/2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Newcastle University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- AFRD School, Study director, School of Agriculture, Food and Rural development
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02701959
- Sponsor's protocol ID
- 15-QAD-15
- Acronym
- LBP
- Status last verified
- May 2016
- First submitted
- 17 Feb 2016
- Last updated
- 23 May 2016
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No: I can't share the individual participants data because of the privacy of volunteers have been participated in this study and this already been mentioned in the application form of ethical approval.
Publications
Qadir OK, Seal CJ, Ashor AW, Tassotti M, Mena P, Del Rio D, Siervo M, Brandt K. Double-blind controlled dietary cross-over intervention with differentially fertilised intact lettuce leaves shows acute reduction in blood pressure in young adults, associated with faster uptake of nitrate than of phenolics. Eur J Nutr. 2022 Dec;61(8):4191-4203. doi: 10.1007/s00394-022-02961-5. Epub 2022 Jul 23.
PubMed 35871120
Study at a glance
From the registry record, last updated by the sponsor on 23 May 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Growth of Lettuce With Different Content of Inorganic Nitrate as a Feeding Strategy for Placebo-controlled Nutritional Interventions to Test the Effects of Inorganic Nitrate on Human Health
- ClinicalTrials.gov ID
- NCT02701959
- Acronym / sponsor ID
- LBP / 15-QAD-15
- Conditions
- Dietary Modification, Blood Pressure
- Keywords
- Nitric oxide, Dietary intervention trail
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Newcastle UniversityUniversity, hospital or other
- Study start
- Apr 2015
- Primary completion
- Aug 2015 (actual)
- Study completion
- Aug 2015 (actual)
- First posted
- 8 Mar 2016 (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.
Leafy vegetables are a natural source of dietary nitrate, which may reduce systolic blood pressure (BP). However, the evidence has been obtained from studies using nitrate solutions (i.e., potassium or sodium nitrate) or beetroot juice supplementation which have a suitable placebo for the design of double-blind clinical trials. However, the design of food-based nutritional interventions is complicated by the fact that an appropriate placebo treatment is not available and, therefore, it is not possible to meet the criteria for proper double-blind randomised placebo-controlled intervention trials. In addition, the biological effects of processed products such as beetroot juice or solutions with a pharmacological grade may be different from that of fresh vegetables, e.g. due to conversion of nitrate to nitrite in the mouth during chewing.
Objectives: to investigate whether two sets of lettuce specifically grown with different nitrate content but otherwise similar composition show different effects on nitrate uptake and bioavailability in humans. Additionally, the investigators also aim to design human intervention studies to investigate the effect of intake of lettuce with different nitrate content on vascular health.
These objectives will be tested by growing lettuce with different fertiliser compositions resulting in high and low nitrate content and then investigating the bioavailability and short-term effect on BP in healthy young volunteers in a double-blind cross-over design. Eligible subjects will consume one meal each of either low or high nitrate lettuce. Urine, blood and saliva samples will be collected at baseline, for 6 hours after the ingestion and then again after 24hr. Blood Pressure BP will be measured continuously for 24 hours starting at baseline. The volunteers will repeat the intervention with the second treatment.
Detailed description
Study Design and Subjects: This study is designed as a double-blind, randomized, crossover, intervention trial in which thirty healthy young volunteers (BMI: 20-25 kg/m2), non-smoking subjects (age: 18-35 years) will be recruited. In each of two intervention periods, subjects will be asked to eat 50g of either high nitrate lettuce or low nitrate lettuce (placebo) on a single occasion (the second visit) with dietary restriction for 3 days prior to the second visit and in the 24 hr period following after the consumption, concluded with a third visit, with at least 3 weeks washout period before the second 2-day intervention period. Urine, saliva and blood samples will be collected during a 6-hour period during the second visit. Urine samples will be collected during 24h from consumption until the third visit, to assess the pharmacokinetics and bioavailability and compliance to the interventions (details in the diagram of human trial).
The primary outcomes are 24-hour BP and nitrate content in urine, plasma and saliva. Samples will be collected into tubes and then analysed in the laboratory for the nitrate content (NO3-) by gas chromatography-mass spectroscopy (GCMS). Participants will follow specific dietary and lifestyle instructions to minimise confounding effects.
Participant will receive a small honorarium after the study and reasonable travel expenses will be reimbursed.
Dietary Interventions: Participants will be asked to arrive fasting in the morning of the second (main) visit and will consume a standard meal (Chicken Hotpot from ASDA) with the same drink water at the evening before and the evening after the visit, as well as following a diet that excludes a list of specific foods containing high nitrate (rocket, spinach, other leafy vegetables, radish and beet root), cured meat, cured seafood and cured fish, mature cheese for 24hr prior to the study and fasting on the morning of the study.
Anthropometry: This includes the measurements of body weight, height and waist circumference according to standardised protocols. Procedures are safe, not invasive and induce minimal discomfort for the participants.
Body Composition: This includes the measurement of body fat and muscle using a non-invasive technique called bio impedance analysis using a leg-to-leg bioelectrical impedance device (TANITA 300 MA). The procedure is safe, non-invasive and induces minimal discomfort for the participant. The duration of the measurement is of approximately 3-5 minutes.
24-hr BP monitoring: participants will be fitted with an automated portable device to measure BP over a 24-hr period. Participants will be instructed on how to safely operate the device. The measurement are safe and minimally invasive. BP readings will be recorded every 30 minutes during day time and every hour during the night to minimise the potential impact on sleep quality.
Urine samples: The first morning void (FMV) will be collected at home (pre supplementation) and after arrival full urine samples (all that the volunteer is able to produce) at set times before and after the supplementation (between baseline and 6hr) at NU-Food research facility. Subsequent collections afterwards (between 6-12hr and 12-24 hr) will take place at home in appropriate plastic containers and the samples will be collected at the final visit 24hr after the consumption. After measuring the volume of each sample, sub samples will be stored for analysis and for calculation of pharmacokinetics.
Saliva samples: a small saliva sample (~2ml) will be collected in disposable plastic containers at baseline and at every hour for 6 hours at NU-Food research facility; and then after 9 and 12 hour at home, with the final sample taken after 24 hr.
Blood Samples: Venous blood samples (LH 6 ml) will be collected at baseline, three and six hours post supplementation of treatments and then again after 24 hr.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Low nitrate lettuce | Placebo comparator | Dietary Supplement: Low Nitrate Lettuce50g of low nitrate lettuce (placebo) on single occasions |
| High nitrate lettuce | Active comparator | Dietary Supplement: High Nitrate Lettuce50g of high nitrate lettuce (intervention) on single occasions |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- The investigators aim to recruit 20 healthy young volunteers, non-smoking, male and female aged 18-35 years with a body mass index (BMI) in the range of 20 to 25 kg/m2.
Key exclusion criteria (12 listed)
- Current participation in other clinical investigations.
- Mouthwash users.
- Vegetarianism (likely to have very high nitrate intake)
- Dislike to lettuce consumption or inability to comply with the study diet (lack of compliance)
- Use of antihypertensive or cholesterol lowering medication.
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 |
|---|---|---|
| High Nitrate LettuceThe lettuce has been grown with high concentration of nitrogen fertilizer (150ppm) to produce the high of nitrate content in the lettuce, the nitrate content of 50 grams of high nitrate lettuce was (~530 mg nitrate derived). | Dietary supplement | High nitrate lettuce |
| Low Nitrate LettuceThe lettuce has been grown with low concentration of nitrogen fertilizer (25ppm) to produce the low amount of nitrate in the lettuce, the nitrate content of 50 grams of high nitrate lettuce was (~3 mg nitrate derived). | Dietary supplement | Low nitrate lettuce |
Primary outcome
Change in 24-hour Ambulatory Blood Pressure (AMBP)
Time frame: Baseline and 24 hours
Change in Systolic and Diastolic Blood Pressure at baseline and every 30 minutes at day time and every hour at night time for 24 hours.
5 secondary outcomes
Change in bio-availability of nitrate and nitrite in plasma
Time frame: 24 hours
Change in Cyclic Guanosine Monophosphate (cGMP) in plasma samples
Time frame: 24 hours
Change in bio-availability of nitrate and nitrite in urine samples
Time frame: 24 hours
Change in bio-availability of nitrate and nitrite in saliva samples
Time frame: 24 hours
Change in Antioxidant capacity of Ferric Reducing Antioxidant Power (FRAP) and Trolox Equivalent Antioxidant Capacity (TEAC) in plasma samples.
Time frame: 24 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 23 May 2016.
- Derived from this study: PubMed 35871120Qadir OK, Seal CJ, Ashor AW, Tassotti M, Mena P, Del Rio D, Siervo M, Brandt K. Double-blind controlled dietary cross-over intervention with differentially fertilised intact lettuce leaves shows acute reduction in blood pressure in young adults, associated with faster uptake of nitrate than of phenolics. Eur J Nutr. 2022 Dec;61(8):4191-4203. doi: 10.1007/s00394-022-02961-5. Epub 2022 Jul 23.
- Individual participant dataSharing planned: No. I can't share the individual participants data because of the privacy of volunteers have been participated in this study and this already been mentioned in the application form of ethical approval.
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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.
AFRD School study director
School of Agriculture, Food and Rural development
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing High Nitrate Lettuce and Low Nitrate Lettuce in people with Dietary Modification and Blood Pressure, run by Newcastle University at 1 site in United Kingdom.
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 1 inclusion and 12 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 23 May 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
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.
What does this combined 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.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
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?
Change in 24-hour Ambulatory Blood Pressure (AMBP) (time frame: Baseline and 24 hours). 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 NCT02701959, 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 23 May 2016.