AchalasiaPhase 4NCT05550194
VZV in the Enteric Nervous System: Pathogenesis and Consequences
A Phase 4 study testing ValACYclovir 1000 MG and Shingrix in people with Achalasia, run by Vanderbilt University Medical Center at 1 site in United States.
Trial summary
Varicella zoster virus (VZV) is the cause of chickenpox and shingles, but it also infects, becomes latent, and reactivates in nerve cells of the bowel to cause a gastrointestinal disorder ("enteric shingles"). Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Achalasia
- What is being tested?
- ValACYclovir 1000 MG and Shingrix
- Type of treatment
- Vaccines
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Mar 2023to Aug 2027
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
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 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male and female subjects aged 18-75 years old inclusive (females of childbearing potential should be on highly effective contraceptive methods)
- Fluent in English and mentally capable to provide informed consent who present to Vanderbilt University Medical Center Digestive Diseases Center for treatment of achalasia.
- Based on standard clinical practice, we anticipate that patients who undergo these treatments will have been formally diagnosed with achalasia and will be fit to undergo the selected treatment intervention.
- All subjects must be able to undergo timed barium swallow testing, trans-nasal intubation for high-resolution manometry probe, and therapeutic intervention of a 2-month course of valacyclovir 1g TID and two injections of Shingrix over a two-month period.
Who cannot join
- Unstable medical illness with ongoing diagnostic work-up and treatment. Patients with well-controlled hypertension, diabetes and a remote history of ischemic heart disease that is deemed stable, as judged by the physician-investigator can be included.
- Current neurologic or cognitive impairment which would make the patient an unsuitable candidate for a research trial.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Vanderbilt University Medical Center
Nashville, Tennessee, 37129
Michael McGill, 615-322-4643, michael.g.mcgill@vumc.org
Amy Motley, 615-322-6281, amy.motley@vumc.org
About this study
Varicella zoster virus (VZV) is the cause of chickenpox and shingles, but it also infects, becomes latent, and reactivates in nerve cells of the bowel to cause a gastrointestinal disorder ("enteric shingles"). The Investigators recently found that a chronic active VZV infection, a form of enteric shingles, is associated with achalasia, a severe disease in which the passage of food from esophagus to stomach is impaired. We now propose to eradicate VZV to determine whether its association with achalasia is causal, to identify the genetic basis behind VZV reactivation in the esophagus, and the relationship of mast cells to enteric shingles and abdominal pain.
Read the detailed description
Varicella zoster virus (VZV) is so well known as the cause of cutaneous varicella (chickenpox) and zoster (shingles) that it can be hard to imagine it as an enteric pathogen. VZV establishes latency during varicella and returns to the skin in zoster when the neurons in which VZV reactivates have cutaneous projections. Because a viremia occurs during varicella, VZV also infects and establishes latency in enteric neurons that do not innervate the skin. VZV can reactivate in enteric neurons to give rise to "enteric zoster", which can occur without an associated rash. Because a rash may thus be absent, pain due to enteric zoster can be occult. The Investigators have found, however, that VZV DNA, which is absent from normal saliva, is detectable in saliva whenever an active (lytic) VZV infection is present in the body; thus, detection of salivary VZV is a non- invasive diagnostic tool that, in combination with enteric signs and symptoms, helps to identify GI disorders that involve VZV. The Investigators have found VZV transcripts and protein in endoscopic biopsies from patients with occult abdominal pain and salivary VZV DNA, which verifies that these patients have enteric zoster. These observations led the Investigators to investigate the potential association between VZV and achalasia in 15 patients.
The Investigators found salivary VZV DNA in 12/15 subjects examined prior to myotomy and, subsequently, VZV transcripts in 13/15 of the resected myotomy specimens. The tissue also contained VZV immunoreactive (gE, gH, ORF40p) neurons, nerve fibers, and multinucleated giant cells. To help determine whether this persistent VZV infection of esophageal neurons is causally related to achalasia, the Investigators now propose to conduct a clinical trial of valacyclovir to determine whether eradication of VZV alleviates achalasia symptoms and improves esophageal function. The Investigators also plan to quantify viral load in relation to achalasia phenotypes and employ next generation sequencing to look for a genetic basis of esophageal VZV reactivation. Finally, because mast cell accumulation and degranulation have been reported in the achalasia esophagus and verified in our preliminary data, the Investigators will test the hypothesis that mast cell activation contributes to manifestations and/or painful symptoms of VZV- associated achalasia. To gain insight into mechanisms of achalasia pathogenesis, the Investigators will also determine whether VZV reactivates specifically in neurons thought to control relaxation of the lower esophageal sphincter (nitric oxide synthase) and/or the excitatory phase of esophageal peristalsis (choline acetyltransferase). Viral destruction of nitrergic inhibitory neurons could be a cause of failure of LES smooth muscle to relax and either or both of these neurons could contribute to the loss of peristalsis that accompanies achalasia.
- Conditions
- Achalasia
- Being tested
- ValACYclovir 1000 MG, Shingrix
- Medical subject headings
- Esophageal Achalasia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ValACYclovir 1000 MGDrug
Also called Valtrex
Valacyclcovir is a targeted anti-viral for varicella zoster virus (VZV).
ShingrixBiological
Also called Zoster vaccine recombinant
Vaccine indicated for prevention of herpes zoster
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Experimental | Patients with Achalasia (phenotypes II and III) with VZV DNA in saliva. Patients will be treated with valacyclovir 3 times per day. Patients found to benefit from treatment with valacyclovir will be offered Shingrix vaccine (2 - 0.5mL doses) Receives: Drug: ValACYclovir 1000 MG; Biological: Shingrix |
What is being measured
The primary outcome is the main question the study is designed to answer.
Response of VZV-associated achalasia to anti-VZV therapy.
Response will be measured by the Eckardt score. The Eckardt score is the sum of the symptom scores for dysphagia, regurgitation, and chest pain (with a score of 0 indicating the absence of symptoms, 1 indicating occasional symptoms, 2 indicating daily symptoms, and 3 indicating symptoms at each meal) and weight loss (with 0 indicating no weight loss, 1 indicating a loss of <5 kg, 2 indicating a loss of 5 to 10 kg, and 3 indicating a loss of >10 kg).
Measured: 4 months
Secondary outcomes (3)
Difference in viral loads in achalasia phenotype II versus phenotype III
Difference in viral load will be measured by real-time qPCR to quantify VZV transcripts (ORF40, ORF67) to estimate the severity of VZV infection.
Measured: One year
Genetic typing of reactivation of VZV in the esophagus
Next-generation sequencing will generate whole VZV genomes from the low amounts of DNA found in clinical samples for VZV genotyping
Measured: One year
Incidence of reactivation of VZV due to mast cell degranulation
Number of subjects found to have mast cell disorder
Measured: One year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Sep 2022
- Study start27 Mar 2023
- Primary completionAug 2027 (estimated)
- Study completionAug 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AchalasiaStudies of the same condition, open and under way.
- More trials run by Vanderbilt University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Patients with Achalasia (phenotypes II and III) with VZV DNA in saliva
- Masking
- None (open label)
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Columbia University
- Responsible party
- Principal investigator, Michael Vaezi, Vanderbilt University Medical Center
- Investigators
- Michael Vaezi, MD, Principal investigator, Vanderbilt University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05550194
- Sponsor's protocol ID
- VENS_220945
- Status last verified
- Oct 2026
- First submitted
- 19 Sep 2022
- Last updated
- 5 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Yes The investigators agree to the timely release and sharing of information to be no later than the acceptance for publication of the main findings from the final data set. Investigators are also committed to ensuring that all data are free of identifiers that would permit linkage to individual research participation as well as variables that could lead to deductive disclosure of individual subjects.
Study at a glance
From the registry record, last updated by the sponsor on 5 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- VZV in the Enteric Nervous System: Pathogenesis and Consequences
- ClinicalTrials.gov ID
- NCT05550194
- Acronym / sponsor ID
- VENS_220945
- Conditions
- Achalasia
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Vanderbilt University Medical CenterUniversity, hospital or other
- Collaborators
- Columbia University
- Study start
- 27 Mar 2023 (actual)
- Primary completion
- Aug 2027 (estimated)
- Study completion
- Aug 2027 (estimated)
- First posted
- 22 Sep 2022 (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.
Varicella zoster virus (VZV) is the cause of chickenpox and shingles, but it also infects, becomes latent, and reactivates in nerve cells of the bowel to cause a gastrointestinal disorder ("enteric shingles"). The Investigators recently found that a chronic active VZV infection, a form of enteric shingles, is associated with achalasia, a severe disease in which the passage of food from esophagus to stomach is impaired. We now propose to eradicate VZV to determine whether its association with achalasia is causal, to identify the genetic basis behind VZV reactivation in the esophagus, and the relationship of mast cells to enteric shingles and abdominal pain.
Detailed description
Varicella zoster virus (VZV) is so well known as the cause of cutaneous varicella (chickenpox) and zoster (shingles) that it can be hard to imagine it as an enteric pathogen. VZV establishes latency during varicella and returns to the skin in zoster when the neurons in which VZV reactivates have cutaneous projections. Because a viremia occurs during varicella, VZV also infects and establishes latency in enteric neurons that do not innervate the skin. VZV can reactivate in enteric neurons to give rise to "enteric zoster", which can occur without an associated rash. Because a rash may thus be absent, pain due to enteric zoster can be occult. The Investigators have found, however, that VZV DNA, which is absent from normal saliva, is detectable in saliva whenever an active (lytic) VZV infection is present in the body; thus, detection of salivary VZV is a non- invasive diagnostic tool that, in combination with enteric signs and symptoms, helps to identify GI disorders that involve VZV. The Investigators have found VZV transcripts and protein in endoscopic biopsies from patients with occult abdominal pain and salivary VZV DNA, which verifies that these patients have enteric zoster. These observations led the Investigators to investigate the potential association between VZV and achalasia in 15 patients.
The Investigators found salivary VZV DNA in 12/15 subjects examined prior to myotomy and, subsequently, VZV transcripts in 13/15 of the resected myotomy specimens. The tissue also contained VZV immunoreactive (gE, gH, ORF40p) neurons, nerve fibers, and multinucleated giant cells. To help determine whether this persistent VZV infection of esophageal neurons is causally related to achalasia, the Investigators now propose to conduct a clinical trial of valacyclovir to determine whether eradication of VZV alleviates achalasia symptoms and improves esophageal function. The Investigators also plan to quantify viral load in relation to achalasia phenotypes and employ next generation sequencing to look for a genetic basis of esophageal VZV reactivation. Finally, because mast cell accumulation and degranulation have been reported in the achalasia esophagus and verified in our preliminary data, the Investigators will test the hypothesis that mast cell activation contributes to manifestations and/or painful symptoms of VZV- associated achalasia. To gain insight into mechanisms of achalasia pathogenesis, the Investigators will also determine whether VZV reactivates specifically in neurons thought to control relaxation of the lower esophageal sphincter (nitric oxide synthase) and/or the excitatory phase of esophageal peristalsis (choline acetyltransferase). Viral destruction of nitrergic inhibitory neurons could be a cause of failure of LES smooth muscle to relax and either or both of these neurons could contribute to the loss of peristalsis that accompanies achalasia.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Patients with Achalasia (phenotypes II and III) with VZV DNA in saliva
| Arm | Type | Receives |
|---|---|---|
| Treatment | Experimental | Drug: ValACYclovir 1000 MG, Biological: ShingrixPatients with Achalasia (phenotypes II and III) with VZV DNA in saliva. Patients will be treated with valacyclovir 3 times per day. Patients found to benefit from treatment with valacyclovir will be offered Shingrix vaccine (2 - 0.5mL doses) |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Male and female subjects aged 18-75 years old inclusive (females of childbearing potential should be on highly effective contraceptive methods)
- Fluent in English and mentally capable to provide informed consent who present to Vanderbilt University Medical Center Digestive Diseases Center for treatment of achalasia.
- Based on standard clinical practice, we anticipate that patients who undergo these treatments will have been formally diagnosed with achalasia and will be fit to undergo the selected treatment intervention.
- All subjects must be able to undergo timed barium swallow testing, trans-nasal intubation for high-resolution manometry probe, and therapeutic intervention of a 2-month course of valacyclovir 1g TID and two injections of Shingrix over a two-month period.
Key exclusion criteria (2 listed)
- Unstable medical illness with ongoing diagnostic work-up and treatment. Patients with well-controlled hypertension, diabetes and a remote history of ischemic heart disease that is deemed stable, as judged by the physician-investigator can be included.
- Current neurologic or cognitive impairment which would make the patient an unsuitable candidate for a research trial.
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 |
|---|---|---|
| ValACYclovir 1000 MGAlso: ValtrexValacyclcovir is a targeted anti-viral for varicella zoster virus (VZV). | Drug | Treatment |
| ShingrixAlso: Zoster vaccine recombinantVaccine indicated for prevention of herpes zoster | Biological | Treatment |
Primary outcome
Response of VZV-associated achalasia to anti-VZV therapy.
Time frame: 4 months
Response will be measured by the Eckardt score. The Eckardt score is the sum of the symptom scores for dysphagia, regurgitation, and chest pain (with a score of 0 indicating the absence of symptoms, 1 indicating occasional symptoms, 2 indicating daily symptoms, and 3 indicating symptoms at each meal) and weight loss (with 0 indicating no weight loss, 1 indicating a loss of <5 kg, 2 indicating a loss of 5 to 10 kg, and 3 indicating a loss of >10 kg).
3 secondary outcomes
Difference in viral loads in achalasia phenotype II versus phenotype III
Time frame: One year
Genetic typing of reactivation of VZV in the esophagus
Time frame: One year
Incidence of reactivation of VZV due to mast cell degranulation
Time frame: One year
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Oct 2026.
- Individual participant dataSharing planned: Yes. Yes The investigators agree to the timely release and sharing of information to be no later than the acceptance for publication of the main findings from the final data set. Investigators are also committed to ensuring that all data are free of identifiers that would permit linkage to individual research participation as well as variables that could lead to deductive disclosure of individual subjects.
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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.
Michael Vaezi, MD principal investigator
Vanderbilt University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing ValACYclovir 1000 MG and Shingrix in people with Achalasia, run by Vanderbilt University Medical Center 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 4 inclusion and 2 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: looking for participants now, as of the sponsor's last update on 5 Oct 2026. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Michael McGill, BS (6153224643, michael.g.mcgill@vumc.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Response of VZV-associated achalasia to anti-VZV therapy. (time frame: 4 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 5 Oct 2026.