Vitamin A DeficiencyGVASNCT04438200
Liver and Bone Retinol Levels in Guatemalan Adolescents and Adults
An observational study of Vitamin A Deficiency and Vitamin A Toxicity, run by Newcastle University at 5 sites in 2 countries.
Trial summary
Guatemala has enforced mandatory fortification of sugar with vitamin A (VA) since June 1974 and has led to a highly successful reduction in VA deficiency and associated disease. However, Ribaya-Mercado et al. Read more about this study
- Who is it for?
- Ages 10 years and olderHealthy volunteers can take part
- Conditions the study is for
- Vitamin A Deficiency, Vitamin A Toxicity, Hypervitaminosis A
- How many people
- 150 participants
- Where
- 5 sitesin 2 countries
- Study dates
- 24 Oct 2019to Jul 2020
- Phase
- Observational
- 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 10 years and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: Guatemalan cadavers, from 2 hospitals in Guatemala City, aged >10 years with a non-metabolic cause of death, within 24 hours of death
Who may be able to join
- Aged >10 years
- Non-metabolic cause of death (e.g. accidents, trauma, or violence from firearms, stabbings, cranial and other trauma, asphyxiation etc.)
- No longer than 24 hours since the time of death
- Lived in Guatemala (exposure to fortified sugar)
Who cannot join
- Aged <10 years
- Individuals with metabolic or nutritional conditions (diabetes, dyslipidemias, chronic alcoholism, etc.)
- Longer than 24 hours since the time of death
- Not Guatemalan resident (Tourist, visitor etc.)
Trial locations and contacts
5 sites in 2 countries.
5 sites in 2 countries
Guatemala4 sites, 4 recruiting
- Recruiting
Hospital Roosevelt
Guatemala City, Zona 11
Keyla Castellanos, MD, knca9510@gmail.com
Francisco Chew, MD, chewf5@gmail.com
- Recruiting
INCAP
Guatemala City, Zona 11
Francisco Chew, MD, chewf5@gmail.com
Keyla Castellanos, MD, knca9510@gmail.com
- Recruiting
Hospital General San Juan de Dios
Guatemala City, Zona 1
Keyla Castellanos, MD, knca9510@gmail.com
Francisco Chew, MD, chewf5@gmail.com
- Recruiting
Morgue del INACIF
Guatemala City, Zona 3
Keyla Castellanos, MD, knca9510@gmail.com
Francisco Chew, MD, chewf5@gmail.com
United Kingdom1 site
- Active, not recruiting
Newcastle University
Newcastle upon Tyne, Tyne and Wear, NE2 4HH
About this study
Official title: Niveles de Retinol Hepatico y óseo en cadáveres de Adolescentes y Adultos Guatemaltecos (Liver and Bone Retinol Levels in Guatemalan Adolescents and Adults)
Guatemala has enforced mandatory fortification of sugar with vitamin A (VA) since June 1974 and has led to a highly successful reduction in VA deficiency and associated disease. However, Ribaya-Mercado et al. 2014, estimated the biological impact of sugar fortified with retinyl palmitate that there may be a risk of chronic excess intake of preformed VA associated with programs of mass fortification. A recent food consumption survey in two departments in Guatemala found the average daily sugar intake in children under the age of two who aren´t being breastfed is 30.3 g, which translates into a daily intake of 272 μg of retinol (almost the full estimated average requirement (EAR) for that age group). Since data from the second National Survey on Micronutrients suggest a risk of VA toxicity, it is important to determine the levels of hepatic VA directly in corpses of individuals, of all ages, who have died of non-metabolic causes. Due to this, the investigators propose to assess liver and bone VA levels in combination with gene expression, histopathology and biochemical analyses, to elicit indications of hypervitaminosis A in Guatemala.
Read the detailed description
Objectives:
- To determine the post mortem concentration of hepatic and bone VA in corpses of adolescent, young and elderly adults as an indicator of exposure to dietary VA
- To assess the effect of high VA exposure on key enzymes in liver and bone tissue and to assess the risk of hypervitaminosis A in people exposed to compulsory mass vitamin A fortification program in Guatemala.
Methodology:
Setting and sampling The corpses for this study will be obtained from the National Institute of Forensic Sciences' (INACIF) departmental morgues in 2 hospitals in Guatemala City. The study population will be 150 cadavers sampled for VA tissue concentration; gene expression analysis combined with histopathology.
Sample collection process and duration All samples will be collected during necropsies carried out at the INACIF forensic morgue. During necropsy, the liver will be weighed and the information recorded. A range of up to 10 x 3 g samples of the liver's right lobe will be obtained. Each sample will be properly labelled with previously prepared codes. Liver samples for histopathological analysis will be stored in 10% buffered formalin for 24 hours prior to transfer to ethanol before embedding, sectioning and staining. All samples collected for retinoid analysis will be frozen on dry ice in the morgue, transported as such to the laboratory and subsequently stored at -80˚C. Liver samples for gene expression analysis will be collected in RNAlater solution to protect RNA stability and subsequently stored at -80˚C until shipment to Newcastle University. The hepatic VA analysis will be done in Newcastle University using established High Perfromance Liquid Chromatography (HPLC) methods. Samples for analysis of gene expression will be sent on dry ice to Newcastle for RNA extraction and quantification. Since it is possible to obtain good quality RNA suitable for Quantitative Polymerase Chain Reaction (q-PCR) based analyses from post mortem tissue up to 72 hours after death, tissue samples stored in RNAlater within 24 hours of death will be adequate for gene expression analysis. Furthermore, experience from the investigators human biobank in Newcastle shows that tissue RNA can be extracted successfully after the demise of a patient up to 72 hours after death as long as the tissue has a pH of over 6. Gene expression of key regulatory proteins, such as LRAT and CYP26A1 will be performed in Newcastle. Choice of genes was based on the fact that LRAT may become saturated at very high levels of VA, leading to increasing levels of free circulating VA that can be metabolized to retinoic acid and other metabolites via CYP26A. Histopathological analysis will be carried out by pathologists in Guatemala with digitised slides being sent to the pathologist within Newcastle University - these slides will be analysed by both pathologists independently.
Bone samples will also be obtained during the necropsy carried out at the INACIF forensic morgue. The iliac crest bone will be exposed by making an incision and removing the overlying soft tissue (skin, adipose tissue, connective tissue and muscle). The periosteum and cortical bone shall be removed via osteotomy exposing the spongy bone. Biopsy needles will be used to take samples from the spongy bone for analysis of tissue VA concentrations and gene expression, as previously described, at Newcastle University.
All samples will be shipped to Newcastle University on dry ice.
Study duration According to the information provided by INACIF 18 autopsies were performed between March and May 2013 on children less than one year of age, 24 on children from 1 to 4 years old, 11 on children 5 to 9 years old, 51 on individuals from 10 to 14 years old, 281 on adolescents 15 to 19 years old, and 401 on young adults 20 to 24 years old. According to INACIF's forensic doctor, ~60% of the total number of autopsies carried out in Guatemala are performed in the capital city. The main causes of death in children under the age of 9 were head injuries and other types of trauma. Individuals from 10 to 24 years of age died mainly due to violence: firearms, stabbings, choking and different types of trauma.
- Conditions
- Vitamin A Deficiency, Vitamin A Toxicity, Hypervitaminosis A
- Keywords
- Retinol, Hypervitaminosis A, Hepatic Vitamin A, Guatemala
- Medical subject headings
- Vitamin A Deficiency, Hypervitaminosis A
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Adolescents | Individuals aged 10-19 years | |
| Young Adults | Individuals aged 20-39 years | |
| Elderly Adults | Individuals aged 40+ years |
What is being measured
The primary outcome is the main question the study is designed to answer.
Liver Vitamin A concentration
Liver Vitamin A concentration
Measured: Enrolment
Liver Gene Expression
Gene expression associated with Vitamin A
Measured: Enrolment
Liver Histology
Histological changes associated with Vitamin A
Measured: Enrolment
Bone Gene Expression
Gene expression associated with Vitamin A
Measured: Enrolment
Secondary outcomes (1)
Bone Vitamin A concentration
Bone Vitamin A concentration
Measured: Enrolment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2020
- Study start24 Oct 2019
- Primary completionJul 2020 (estimated)
- Study completionJul 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Vitamin A DeficiencyStudies 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
- Observational
- Observational model
- Other
- Time perspective
- Cross-sectional
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Newcastle University
- Sponsor type
- University, hospital or other
- Collaborators
- Bill and Melinda Gates Foundation, HarvestPlus, Institute of Nutrition of Central America and Panama, INACIF
- Responsible party
- Sponsor
- Investigators
- Francisco Chew, MD, Principal investigator, Institute of Nutrition of Central America and PanamaErick Boy, MD, PhD, Principal investigator, HarvestPlusGeorg Lietz, PhD, Study director, Newcastle University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04438200
- Sponsor's protocol ID
- VDACS-MF-0109-2019
- Acronym
- GVAS
- Status last verified
- Feb 2020
- First submitted
- 23 Mar 2020
- Last updated
- 18 Jun 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Pineda, O. (1998). Fortification of Sugar with Vitamin A. Food and Nutrition Bulletin, 19(2), 131-136.
Ribaya-Mercado JD, Solomons NW, Medrano Y, Bulux J, Dolnikowski GG, Russell RM, Wallace CB. Use of the deuterated-retinol-dilution technique to monitor the vitamin A status of Nicaraguan schoolchildren 1 y after initiation of the Nicaraguan national program of sugar fortification with vitamin A. Am J Clin Nutr. 2004 Nov;80(5):1291-8. doi: 10.1093/ajcn/80.5.1291.
PubMed 15531678Olsen K, Suri DJ, Davis C, Sheftel J, Nishimoto K, Yamaoka Y, Toya Y, Welham NV, Tanumihardjo SA. Serum retinyl esters are positively correlated with analyzed total liver vitamin A reserves collected from US adults at time of death. Am J Clin Nutr. 2018 Nov 1;108(5):997-1005. doi: 10.1093/ajcn/nqy190.
PubMed 30475970
Study at a glance
From the registry record, last updated by the sponsor on 18 Jun 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Niveles de Retinol Hepatico y óseo en cadáveres de Adolescentes y Adultos Guatemaltecos (Liver and Bone Retinol Levels in Guatemalan Adolescents and Adults)
- ClinicalTrials.gov ID
- NCT04438200
- Acronym / sponsor ID
- GVAS / VDACS-MF-0109-2019
- Conditions
- Vitamin A Deficiency, Vitamin A Toxicity, Hypervitaminosis A
- Keywords
- Retinol, Hypervitaminosis A, Hepatic Vitamin A, Guatemala
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Newcastle UniversityUniversity, hospital or other
- Collaborators
- Bill and Melinda Gates Foundation, HarvestPlus, Institute of Nutrition of Central America and Panama, INACIF
- Study start
- 24 Oct 2019 (actual)
- Primary completion
- Jul 2020 (estimated)
- Study completion
- Jul 2020 (estimated)
- First posted
- 18 Jun 2020 (actual)
- 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.
Guatemala has enforced mandatory fortification of sugar with vitamin A (VA) since June 1974 and has led to a highly successful reduction in VA deficiency and associated disease. However, Ribaya-Mercado et al. 2014, estimated the biological impact of sugar fortified with retinyl palmitate that there may be a risk of chronic excess intake of preformed VA associated with programs of mass fortification. A recent food consumption survey in two departments in Guatemala found the average daily sugar intake in children under the age of two who aren´t being breastfed is 30.3 g, which translates into a daily intake of 272 μg of retinol (almost the full estimated average requirement (EAR) for that age group). Since data from the second National Survey on Micronutrients suggest a risk of VA toxicity, it is important to determine the levels of hepatic VA directly in corpses of individuals, of all ages, who have died of non-metabolic causes. Due to this, the investigators propose to assess liver and bone VA levels in combination with gene expression, histopathology and biochemical analyses, to elicit indications of hypervitaminosis A in Guatemala.
Detailed description
Objectives:
- To determine the post mortem concentration of hepatic and bone VA in corpses of adolescent, young and elderly adults as an indicator of exposure to dietary VA
- To assess the effect of high VA exposure on key enzymes in liver and bone tissue and to assess the risk of hypervitaminosis A in people exposed to compulsory mass vitamin A fortification program in Guatemala.
Methodology:
Setting and sampling The corpses for this study will be obtained from the National Institute of Forensic Sciences' (INACIF) departmental morgues in 2 hospitals in Guatemala City. The study population will be 150 cadavers sampled for VA tissue concentration; gene expression analysis combined with histopathology.
Sample collection process and duration All samples will be collected during necropsies carried out at the INACIF forensic morgue. During necropsy, the liver will be weighed and the information recorded. A range of up to 10 x 3 g samples of the liver's right lobe will be obtained. Each sample will be properly labelled with previously prepared codes. Liver samples for histopathological analysis will be stored in 10% buffered formalin for 24 hours prior to transfer to ethanol before embedding, sectioning and staining. All samples collected for retinoid analysis will be frozen on dry ice in the morgue, transported as such to the laboratory and subsequently stored at -80˚C. Liver samples for gene expression analysis will be collected in RNAlater solution to protect RNA stability and subsequently stored at -80˚C until shipment to Newcastle University. The hepatic VA analysis will be done in Newcastle University using established High Perfromance Liquid Chromatography (HPLC) methods. Samples for analysis of gene expression will be sent on dry ice to Newcastle for RNA extraction and quantification. Since it is possible to obtain good quality RNA suitable for Quantitative Polymerase Chain Reaction (q-PCR) based analyses from post mortem tissue up to 72 hours after death, tissue samples stored in RNAlater within 24 hours of death will be adequate for gene expression analysis. Furthermore, experience from the investigators human biobank in Newcastle shows that tissue RNA can be extracted successfully after the demise of a patient up to 72 hours after death as long as the tissue has a pH of over 6. Gene expression of key regulatory proteins, such as LRAT and CYP26A1 will be performed in Newcastle. Choice of genes was based on the fact that LRAT may become saturated at very high levels of VA, leading to increasing levels of free circulating VA that can be metabolized to retinoic acid and other metabolites via CYP26A. Histopathological analysis will be carried out by pathologists in Guatemala with digitised slides being sent to the pathologist within Newcastle University - these slides will be analysed by both pathologists independently.
Bone samples will also be obtained during the necropsy carried out at the INACIF forensic morgue. The iliac crest bone will be exposed by making an incision and removing the overlying soft tissue (skin, adipose tissue, connective tissue and muscle). The periosteum and cortical bone shall be removed via osteotomy exposing the spongy bone. Biopsy needles will be used to take samples from the spongy bone for analysis of tissue VA concentrations and gene expression, as previously described, at Newcastle University.
All samples will be shipped to Newcastle University on dry ice.
Study duration According to the information provided by INACIF 18 autopsies were performed between March and May 2013 on children less than one year of age, 24 on children from 1 to 4 years old, 11 on children 5 to 9 years old, 51 on individuals from 10 to 14 years old, 281 on adolescents 15 to 19 years old, and 401 on young adults 20 to 24 years old. According to INACIF's forensic doctor, ~60% of the total number of autopsies carried out in Guatemala are performed in the capital city. The main causes of death in children under the age of 9 were head injuries and other types of trauma. Individuals from 10 to 24 years of age died mainly due to violence: firearms, stabbings, choking and different types of trauma.
Study design
- Observational model
- Other
- Time perspective
- Cross-sectional
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Adolescents | – | –Individuals aged 10-19 years |
| Young Adults | – | –Individuals aged 20-39 years |
| Elderly Adults | – | –Individuals aged 40+ years |
Who may qualify
- Ages
- 10 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Guatemalan cadavers, from 2 hospitals in Guatemala City, aged >10 years with a non-metabolic cause of death, within 24 hours of death
Key inclusion criteria (4 listed)
- Aged >10 years
- Non-metabolic cause of death (e.g. accidents, trauma, or violence from firearms, stabbings, cranial and other trauma, asphyxiation etc.)
- No longer than 24 hours since the time of death
- Lived in Guatemala (exposure to fortified sugar)
Key exclusion criteria (4 listed)
- Aged <10 years
- Individuals with metabolic or nutritional conditions (diabetes, dyslipidemias, chronic alcoholism, etc.)
- Longer than 24 hours since the time of death
- Not Guatemalan resident (Tourist, visitor etc.)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Liver Vitamin A concentration
Time frame: Enrolment
Liver Vitamin A concentration
Liver Gene Expression
Time frame: Enrolment
Gene expression associated with Vitamin A
Liver Histology
Time frame: Enrolment
Histological changes associated with Vitamin A
Bone Gene Expression
Time frame: Enrolment
Gene expression associated with Vitamin A
1 secondary outcome
Bone Vitamin A concentration
Time frame: Enrolment
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jun 2020.
- BackgroundPineda, O. (1998). Fortification of Sugar with Vitamin A. Food and Nutrition Bulletin, 19(2), 131-136.
- Background: PubMed 15531678Ribaya-Mercado JD, Solomons NW, Medrano Y, Bulux J, Dolnikowski GG, Russell RM, Wallace CB. Use of the deuterated-retinol-dilution technique to monitor the vitamin A status of Nicaraguan schoolchildren 1 y after initiation of the Nicaraguan national program of sugar fortification with vitamin A. Am J Clin Nutr. 2004 Nov;80(5):1291-8. doi: 10.1093/ajcn/80.5.1291.
- Background: PubMed 30475970Olsen K, Suri DJ, Davis C, Sheftel J, Nishimoto K, Yamaoka Y, Toya Y, Welham NV, Tanumihardjo SA. Serum retinyl esters are positively correlated with analyzed total liver vitamin A reserves collected from US adults at time of death. Am J Clin Nutr. 2018 Nov 1;108(5):997-1005. doi: 10.1093/ajcn/nqy190.
- Individual participant dataSharing planned: No
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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.
Francisco Chew, MD principal investigator
Institute of Nutrition of Central America and Panama
Erick Boy, MD, PhD principal investigator
HarvestPlus
Georg Lietz, PhD study director
Newcastle University
5 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Vitamin A Deficiency and Vitamin A Toxicity, run by Newcastle University at 5 sites in 2 countries.
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 4 inclusion and 4 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: status not confirmed, as of the sponsor's last update on 18 Jun 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Guatemala, 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. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Georg Lietz, PhD (00441912086893, georg.lietz@newcastle.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Liver Vitamin A concentration (time frame: Enrolment). 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 NCT04438200, which also lists 3 linked publications.
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 18 Jun 2020.