Parotid Salivary DysfunctionPhase 1NCT00372320
Effect of AdhAQP1 on Salivary Flow in Patients Treated With Radiation for Head and Neck Cancer
A Phase 1 study testing Gene Transfer and AdhAQP1 in people with Parotid Salivary Dysfunction, run by National Institute of Dental and Craniofacial Research (NIDCR) at 1 site in United States.
Trial summary
This study will examine whether the experimental drug AdhAQP1 can increase salivary flow in patients whose parotid glands have been exposed to therapeutic radiation for treatment of head and neck cancer. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Parotid Salivary Dysfunction
- What is being tested?
- Gene Transfer and AdhAQP1
- How many people
- 17 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Sep 2006to 5 Sep 2018
- Phase
- Phase 1
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18 years of age or older.
- Capable of providing informed consent.
- History of radiation therapy for head and neck cancer, having received >45Gy to the parotid gland(s) due to primary or neck radiation.
- Abnormal parotid gland function in the targeted parotid gland as judged by absence of unstimulated parotid salivary flow and a stimulated parotid salivary flow in the targeted parotid gland <0.2 mL/min/gland after 2% citrate stimulation.
- Abnormal (99m)TcO4 scintiscan (reduced or absent uptake of (99m)TcO4) for the targeted parotid gland in the following circumstance: A (99m)TcO4 scintiscan will only be performed and used to determine eligibility if the isotope is available. If the isotope is not available, this inclusion criterion is not applicable.
- Abnormal sialogram (an altered ductal network with sialectasis) for the targeted parotid gland.
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- No current evidence of malignancy by otolaryngology assessment, including a clinical history, nasopharyngolaryngoscopy, and negative CT or PET scan (e.g. reference 58).
- Absence of shedding wild type adenovirus in the saliva sample collected from the targeted gland at the pre-dose visit 1. Specifically, an aliquot of the pre-dose visit 1 saliva sample from the target parotid gland will be used to infect A549 cells to test for the presence of shedding WT Ad virus. If infectious virus emerges during the subsequent 7-10 day follow-up period, then the participant will no longer be eligible for treatment and will be withdrawn from the study. However, if no cytopathic effects are observed over a 7-10 day period, the participant may be treated provided all other eligibility criteria are met. If stimulated saliva cannot be collected at the pre-dose visit 1, this inclusion criterion is not applicable.
- Must be disease-free for at least 5 years, with the disease-free interval calculated from date of last cancer treatment (i.e., date of last radiation, chemotherapy or surgery) to date of pre-dose visit 1.
- Willingness to practice the required birth control method ("barrier" contraception, i.e., condoms, diaphragm) until AdhAQP1 is no longer detectable in their serum or saliva. Women who cannot bear children (post menopausal or due to a surgical intervention) also will be required to practice barrier birth control methods until AdhAQP1 is no longer detectable in their serum or saliva.
- Able to stay at the NIH hospital for the period of time necessary to complete each on-site phase of the protocol.
- No history of allergies to any medications or agents to be used in this protocol.
- On stable doses of medications (greater than or equal to 2 months from the pre-dose visit 1) for any underlying medical conditions.
Who cannot join
- Pregnant or lactating women. Women of childbearing potential are required to have a negative serum pregnancy test at pre-dose visit 1 and a negative urine pregnancy test within 24 hours of treatment.
- Any experimental therapy within 3 months of planned AdhAQP1 administration (Day 1).
- Any active respiratory tract infection in the 3 weeks prior to planned AdhAQP1 administration (Day 1).
- Active infection that requires the use of intravenous antibiotics and does not resolve at least 1 week before planned AdhAQP1 administration (Day 1).
- Evidence of active substance or alcohol abuse or history of substance or alcohol abuse within two years of pre-dose visit 1.
- Uncontrolled ischemic heart disease: unstable angina, evidence of active ischemic heart disease on ECG, congestive heart failure (left ventricular ejection fraction < 45% on MUGA or echo) or cardiomyopathy.
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- Asthma or chronic obstructive pulmonary disease requiring regular inhaled or systemic corticosteroids.
- Individuals taking prescription medications (anti-cholinergics, anti-depressants) likely to result in salivary hypofunction.
- Individuals with a history of autoimmune diseases affecting salivary glands, including Sj(SqrRoot)(Delta)gren s syndrome, lupus, scleroderma, type 1 diabetes, sarcoidosis, amyloidosis, and chronic graft versus host disease.
- Use of systemic immunosuppressive medications, e.g., corticosteroids. Topical corticosteroids are allowed.
- History of a second malignancy, within the past 3 years, with the exception of adequately treated basal cell or squamous cell carcinoma of the skin or in situ carcinoma of the cervix.
- Active hepatitis B, hepatitis C or HIV infection tested using blood collected at pre-dose visit 1.
- WBC <3000/microL or ANC <1500/microL or Hgb <10.0 g/dL or platelets <100,000/microL or absolute lymphocyte count less than or equal to 500/microL using blood collected at pre-dose visit 2.
- ALT and/or AST > 1.5 times the upper limit of normal (ULN) or alkaline phosphatase >1.5 times ULN using blood collected at pre-dose visit 2.
- Serum creatinine > 2 mg/dL using blood collected at pre-dose visit 2.
- Individuals who are active smokers.
- Individuals who consume more than one alcoholic beverage/day.
- Individuals who have an allergy to iodine or shellfish and thus are unable to have sialographic evaluations.
- Individuals whose targeted parotid duct is not clinically accessible on screening sialography evaluations.
- Individuals who on sialography have a distal stenosis in the targeted parotid gland that would impede vector delivery.
- Individuals who likely would require use of a general anesthetic for ultrasound- guided core needle biopsy (applicable only for participants in dose cohorts 2-5).
- Significant concurrent or recently diagnosed (<2 months from Day 1) medical condition that, in the opinion of the Medically Responsible Investigator, could affect the participant's ability to tolerate or complete the study.
- Live vaccines within 4 weeks of first infusion.
- Previous participation in a rAd5 vector gene transfer study.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Open-Label, Dose-Escalation Study Evaluating the Safety of a Single Administration of AdhAQP1, an Adenoviral Vector Encoding Human Aquaporin-1 to One Parotid Salivary Gland in Individuals With Irradiation-Induced Parotid Salivary Hypofunction
This study will examine whether the experimental drug AdhAQP1 can increase salivary flow in patients whose parotid glands have been exposed to therapeutic radiation for treatment of head and neck cancer. Radiation may damage the parotid glands (salivary glands located under the skin in front of the ear), leading to dry mouth, infections, excessive tooth decay, mouth sores, difficulty swallowing and pain. AdhAQP1 contains the human aquaporin-1 gene, which codes for a protein that works to transport water across cells, and a virus that normally can cause colds in humans, but is modified to render it ineffective. In animal experiments, AdhAQP1 has increased saliva production for a short time.
Patients between 18 years of age or older who received radiation treatment for head and neck cancer at least 5 years before enrolling in this study, who have no evidence of recurrent tumor, who have dry mouth and who secrete abnormally low levels of saliva from the parotid glands may be eligible for this study. Candidates are screened with a medical history, physical examination, blood, urine and saliva tests, electrocardiogram (EKG), chest x-ray, MRI exam, gallium scan (a nuclear medicine test to look for inflammation in the salivary glands), technetium pertechnetate scan (a nuclear medicine test to examine salivary gland function), parotid sialogram (x-ray of parotid gland), PET and CT scans to look for signs of tumor and a skin biopsy to collect skin cells for use in immunological tests.
Read more
Participants have a salt and sugar solution infused through a catheter (plastic tube) into both parotid glands. After 10 minutes, the solution drains into the mouth and is swallowed. Saliva is collected from the parotid glands at 6 and 24 hours after administration of the salt and sugar solution. Ten to 14 days later, patients are admitted to the NIH Clinical Center for up to 4 days for the following tests and procedures:
- On the first day, administration, through a catheter, of the study drug AdhAQP1 into one parotid gland.
- Monitoring over the next 3 days for changes in patients' ability to produce saliva. This includes medical examinations and several blood, urine and saliva collections.
- Technetium scan on day 2.
- Gallium scan on day 2.
Patients return to NIH for follow-up visits at 1, 2, 4, and 6 weeks after the AdhAQP1 infusion and then 3, 4, 5, 6 and 12 months for a medical examination and blood, urine and saliva collections. Gallium, technetium and MRI scans are repeated at several of the follow-up visits, and sialograms are done at 6 and 12 months. Chest x-ray and EKG are repeated at 4 and 6 months.
Read the detailed description
The treatment of most head and neck cancer patients includes ionizing radiation (IR). Salivary glands in the IR field suffer irreversible damage. There is no conventional treatment available to correct this condition. Our research group has been developing the AdhAQP1 recombinant serotype 5 adenoviral (rAd5) vector based on the hypothesis that a replication deficient rAd5 vector is capable of safely transferring the human aquaporin-1 (hAQP1) cDNA to parotid glands of adult patients with IR-induced salivary hypofunction, resulting in an elevated salivary output, albeit transiently. Salivary glands have proven to be valuable gene transfer targets in numerous pre-clinical animal model studies. hAQP1, the archetypal water channel, is a plasma membrane protein that facilitates water movement across lipid bilayers. Rat and minipig studies have clearly shown that the AdhAQP1 strategy for restoring salivary flow to IR-damaged salivary glands is effective, and studies in rats, non-human primates and minipigs have shown that AdhAQP1 and similar rAd5 vectors are without significant untoward effects after salivary gland delivery. The purpose of this clinical protocol is to test the safety of AdhAQP1, with some measures of efficacy, in adult patients with established IR-induced parotid gland hypofunction. The targeted tissue site for the AdhAQP1 vector in the proposed study is a single parotid gland. In this Phase 1 dose-escalation study, safety will be evaluated using conventional clinical and immunological parameters. The primary outcome measure for biological efficacy will be parotid gland salivary output.
- Conditions
- Parotid Salivary Dysfunction
- Being tested
- Gene Transfer, AdhAQP1
- Keywords
- Adenovirus, Aquaporin-1, Gene Transfer, Radiation-Induced Salivary Hypofunction, Salivary Gland, Xerostomia, Salivary Dysfunction, Hyposalivation, Dry mouth, head and neck cancer, side effects radiation damage
- Medical subject headings
- Adenoviridae Infections, Xerostomia, Head and Neck Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gene TransferGenetic
AdhAQP1Drug
What is being measured
The primary outcome is the main question the study is designed to answer.
To evaluate the safety of single doses of escalating doses of AdhAQP1
Secondary outcomes (2)
To evaluate the effectiveness of AdhAQP1 to increase parotid gland salivary output and improve symptoms associated with irradiation-induced parotid hypofunction.
To assess salivary flow in the treated parotid gland for up to three years.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Sep 2006 (estimated)
- Study start1 Sep 2006
- Primary completion19 Mar 2014
- Study completion5 Sep 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Parotid Salivary DysfunctionStudies 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
- Primary purpose
- Treatment
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Dental and Craniofacial Research (NIDCR)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Blake M Warner, D.D.S., Principal investigator, National Institute of Dental and Craniofacial Research (NIDCR)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00372320
- Sponsor's protocol ID
- 060206
- Other IDs
- 06-D-0206
- Status last verified
- 5 Sep 2018
- First submitted
- 2 Sep 2006
- Last updated
- 11 Sep 2018
- Results posted
- No
- FDA-regulated drug
- Yes
Publications
Baum BJ, Wellner RB, Zheng C. Gene transfer to salivary glands. Int Rev Cytol. 2002;213:93-146. doi: 10.1016/s0074-7696(02)13013-0.
PubMed 11837896Zufferey R, Aebischer P. Salivary glands and gene therapy: the mouth waters. Gene Ther. 2004 Oct;11(19):1425-6. doi: 10.1038/sj.gt.3302321. No abstract available.
PubMed 15269715Baum BJ, Voutetakis A, Wang J. Salivary glands: novel target sites for gene therapeutics. Trends Mol Med. 2004 Dec;10(12):585-90. doi: 10.1016/j.molmed.2004.10.003.
PubMed 15567328Alevizos I, Zheng C, Cotrim AP, Liu S, McCullagh L, Billings ME, Goldsmith CM, Tandon M, Helmerhorst EJ, Catalan MA, Danielides SJ, Perez P, Nikolov NP, Chiorini JA, Melvin JE, Oppenheim FG, Illei GG, Baum BJ. Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. Gene Ther. 2017 Mar;24(3):176-186. doi: 10.1038/gt.2016.87. Epub 2016 Dec 20.
PubMed 27996967Baum BJ, Zheng C, Alevizos I, Cotrim AP, Liu S, McCullagh L, Goldsmith CM, McDermott N, Chiorini JA, Nikolov NP, Illei GG. Development of a gene transfer-based treatment for radiation-induced salivary hypofunction. Oral Oncol. 2010 Jan;46(1):4-8. doi: 10.1016/j.oraloncology.2009.09.004. Epub 2009 Nov 4.
PubMed 19892587
Study at a glance
From the registry record, last updated by the sponsor on 11 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Open-Label, Dose-Escalation Study Evaluating the Safety of a Single Administration of AdhAQP1, an Adenoviral Vector Encoding Human Aquaporin-1 to One Parotid Salivary Gland in Individuals With Irradiation-Induced Parotid Salivary Hypofunction
- ClinicalTrials.gov ID
- NCT00372320
- Acronym / sponsor ID
- 060206
- Conditions
- Parotid Salivary Dysfunction
- Keywords
- Adenovirus, Aquaporin-1, Gene Transfer, Radiation-Induced Salivary Hypofunction, Salivary Gland, Xerostomia, Salivary Dysfunction, Hyposalivation
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- National Institute of Dental and Craniofacial Research (NIDCR)US National Institutes of Health
- Study start
- 1 Sep 2006
- Primary completion
- 19 Mar 2014 (actual)
- Study completion
- 5 Sep 2018 (actual)
- First posted
- 6 Sep 2006 (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.
This study will examine whether the experimental drug AdhAQP1 can increase salivary flow in patients whose parotid glands have been exposed to therapeutic radiation for treatment of head and neck cancer. Radiation may damage the parotid glands (salivary glands located under the skin in front of the ear), leading to dry mouth, infections, excessive tooth decay, mouth sores, difficulty swallowing and pain. AdhAQP1 contains the human aquaporin-1 gene, which codes for a protein that works to transport water across cells, and a virus that normally can cause colds in humans, but is modified to render it ineffective. In animal experiments, AdhAQP1 has increased saliva production for a short time.
Patients between 18 years of age or older who received radiation treatment for head and neck cancer at least 5 years before enrolling in this study, who have no evidence of recurrent tumor, who have dry mouth and who secrete abnormally low levels of saliva from the parotid glands may be eligible for this study. Candidates are screened with a medical history, physical examination, blood, urine and saliva tests, electrocardiogram (EKG), chest x-ray, MRI exam, gallium scan (a nuclear medicine test to look for inflammation in the salivary glands), technetium pertechnetate scan (a nuclear medicine test to examine salivary gland function), parotid sialogram (x-ray of parotid gland), PET and CT scans to look for signs of tumor and a skin biopsy to collect skin cells for use in immunological tests.
Participants have a salt and sugar solution infused through a catheter (plastic tube) into both parotid glands. After 10 minutes, the solution drains into the mouth and is swallowed. Saliva is collected from the parotid glands at 6 and 24 hours after administration of the salt and sugar solution. Ten to 14 days later, patients are admitted to the NIH Clinical Center for up to 4 days for the following tests and procedures:
- On the first day, administration, through a catheter, of the study drug AdhAQP1 into one parotid gland.
- Monitoring over the next 3 days for changes in patients' ability to produce saliva. This includes medical examinations and several blood, urine and saliva collections.
- Technetium scan on day 2.
- Gallium scan on day 2.
Patients return to NIH for follow-up visits at 1, 2, 4, and 6 weeks after the AdhAQP1 infusion and then 3, 4, 5, 6 and 12 months for a medical examination and blood, urine and saliva collections. Gallium, technetium and MRI scans are repeated at several of the follow-up visits, and sialograms are done at 6 and 12 months. Chest x-ray and EKG are repeated at 4 and 6 months.
Detailed description
The treatment of most head and neck cancer patients includes ionizing radiation (IR). Salivary glands in the IR field suffer irreversible damage. There is no conventional treatment available to correct this condition. Our research group has been developing the AdhAQP1 recombinant serotype 5 adenoviral (rAd5) vector based on the hypothesis that a replication deficient rAd5 vector is capable of safely transferring the human aquaporin-1 (hAQP1) cDNA to parotid glands of adult patients with IR-induced salivary hypofunction, resulting in an elevated salivary output, albeit transiently. Salivary glands have proven to be valuable gene transfer targets in numerous pre-clinical animal model studies. hAQP1, the archetypal water channel, is a plasma membrane protein that facilitates water movement across lipid bilayers. Rat and minipig studies have clearly shown that the AdhAQP1 strategy for restoring salivary flow to IR-damaged salivary glands is effective, and studies in rats, non-human primates and minipigs have shown that AdhAQP1 and similar rAd5 vectors are without significant untoward effects after salivary gland delivery. The purpose of this clinical protocol is to test the safety of AdhAQP1, with some measures of efficacy, in adult patients with established IR-induced parotid gland hypofunction. The targeted tissue site for the AdhAQP1 vector in the proposed study is a single parotid gland. In this Phase 1 dose-escalation study, safety will be evaluated using conventional clinical and immunological parameters. The primary outcome measure for biological efficacy will be parotid gland salivary output.
Study design
- Primary purpose
- Treatment
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
Key exclusion criteria (24 listed)
- Pregnant or lactating women. Women of childbearing potential are required to have a negative serum pregnancy test at pre-dose visit 1 and a negative urine pregnancy test within 24 hours of treatment.
- Any experimental therapy within 3 months of planned AdhAQP1 administration (Day 1).
- Any active respiratory tract infection in the 3 weeks prior to planned AdhAQP1 administration (Day 1).
- Active infection that requires the use of intravenous antibiotics and does not resolve at least 1 week before planned AdhAQP1 administration (Day 1).
- Evidence of active substance or alcohol abuse or history of substance or alcohol abuse within two years of pre-dose visit 1.
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 |
|---|---|---|
| Gene Transfer | Genetic | – |
| AdhAQP1 | Drug | – |
Primary outcome
To evaluate the safety of single doses of escalating doses of AdhAQP1
2 secondary outcomes
To evaluate the effectiveness of AdhAQP1 to increase parotid gland salivary output and improve symptoms associated with irradiation-induced parotid hypofunction.
To assess salivary flow in the treated parotid gland for up to three years.
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 11 Sep 2018.
- Background: PubMed 11837896Baum BJ, Wellner RB, Zheng C. Gene transfer to salivary glands. Int Rev Cytol. 2002;213:93-146. doi: 10.1016/s0074-7696(02)13013-0.
- Background: PubMed 15269715Zufferey R, Aebischer P. Salivary glands and gene therapy: the mouth waters. Gene Ther. 2004 Oct;11(19):1425-6. doi: 10.1038/sj.gt.3302321. No abstract available.
- Background: PubMed 15567328Baum BJ, Voutetakis A, Wang J. Salivary glands: novel target sites for gene therapeutics. Trends Mol Med. 2004 Dec;10(12):585-90. doi: 10.1016/j.molmed.2004.10.003.
- Derived from this study: PubMed 27996967Alevizos I, Zheng C, Cotrim AP, Liu S, McCullagh L, Billings ME, Goldsmith CM, Tandon M, Helmerhorst EJ, Catalan MA, Danielides SJ, Perez P, Nikolov NP, Chiorini JA, Melvin JE, Oppenheim FG, Illei GG, Baum BJ. Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. Gene Ther. 2017 Mar;24(3):176-186. doi: 10.1038/gt.2016.87. Epub 2016 Dec 20.
- Derived from this study: PubMed 19892587Baum BJ, Zheng C, Alevizos I, Cotrim AP, Liu S, McCullagh L, Goldsmith CM, McDermott N, Chiorini JA, Nikolov NP, Illei GG. Development of a gene transfer-based treatment for radiation-induced salivary hypofunction. Oral Oncol. 2010 Jan;46(1):4-8. doi: 10.1016/j.oraloncology.2009.09.004. Epub 2009 Nov 4.
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.
Blake M Warner, D.D.S. principal investigator
National Institute of Dental and Craniofacial Research (NIDCR)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Gene Transfer and AdhAQP1 in people with Parotid Salivary Dysfunction, run by National Institute of Dental and Craniofacial Research (NIDCR) at 1 site in United States.
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 24 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 11 Sep 2018. 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 States. 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.
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?
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?
To evaluate the safety of single doses of escalating doses of AdhAQP1. 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 NCT00372320, which also lists 5 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 11 Sep 2018.