A Randomized Double-Blind Control-Comparison Crossover Trial of Oral Glutamine to Suppress Frequently Recurrent Herpes Labialis

• ClinicalTrials.gov Identifier: NCT00913692
• Recruitment Status: Terminated
• First Posted: June 4, 2009
• Results First Posted: June 11, 2012
• Last Update Posted: June 11, 2012
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): Jeffrey Cohen, National Institutes of Health Clinical Center (CC)

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Prevention
• Conditions: Herpes Labialis; Herpes Simplex Virus
• Interventions: Drug: Glutamine; Drug: Glycine
• Enrollment: 11

Participant Flow

Recruitment Details	Recruitment began in November 2009 at the NIH Clinical Center outpatient clinic. Eleven study participants were enrolled and screened from 11/2009 - 11/2010. Two of these participants proceeded to the treatment phase of the study.
Pre-assignment Details	Participants were enrolled and randomized to the treatment phase only if they met the eligibility criteria after completing the 4 month screening phase. After completion of phase 1 of treatment, there was a 2 week wash out period before beginning phase 2 of treatment.

Arm/Group Title	Glutamine (Study Agent) or Glycine (Placebo)
Arm/Group Description	Participants were enrolled and monitored to document presence of 2 clinically confirmed episodes of herpes labialis, 1 of which must be virologically confirmed, during the screening period. Participants took 15 gm of study agent or placebo by mouth twice daily for 5 months followed by a 2 week wash-out. Then participants took the other agent for another 5 months.
Period Title: Screening (4 Months)
Started	11
Completed	2
Not Completed	9
Reason Not Completed
Physician Decision	3
Not eligible after screening phase.	6
Period Title: Treatment Phase 1 (5 Months)
Started	2
Completed	1
Not Completed	1
Reason Not Completed
Physician Decision	1
Period Title: Washout (2 Weeks)
Started	1
Completed	1
Not Completed	0
Period Title: Treatment Phase 2 (5 Months)
Started	1
Completed	1
Not Completed	0

Baseline Characteristics

Arm/Group Title		Glutamine (Study Agent) or Glycine (Placebo)
Arm/Group Description		Participants were enrolled and monitored to document presence of 2 clinically confirmed episodes of herpes labialis, 1 of which must be virologically confirmed, during the screening period. Participants took 15 gm of study agent or placebo by mouth twice daily for 5 months followed by a 2 week wash-out. Then participants took the other agent for another 5 months.
Overall Number of Baseline Participants		11
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	11 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	11 100.0%
	>=65 years	0 0.0%
Age Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	11 participants
		38 (10.97)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	11 participants
	Female	7 63.6%
	Male	4 36.4%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	11 participants
		11

Outcome Measures

1. Primary Outcome

Title	Does Oral Glutamine Reduce the Number of Recurrences of Herpes Labialis, Diagnosed by Clinical and Microbiologic Criteria, in Healthy Participants With Frequently Recurrent Disease.
Description	During all phases of the study, participants returned to clinic whenever they had a herpes labialis outbreak for staff to assess, obtain a viral swab and document. If unable to return to clinic in the time frame specified in the protocol, participants would take a photo and obtain a swab of the lesion. The number of outbreaks would be measured during each phase.
Time Frame	The screening phase time frame was 4 months. Treatment phase 1 was 5 months. Washout phase was 2 weeks. Treatment phase 2 was 5 months.

Outcome Measure Data

Analysis Population Description

One participant completed the study and one participant started the 1st treatment phase, but was withdrawn during the first treatment phase, hence the primary outcome could not be measured and analyzed.

Arm/Group Title	Glutamine (Study Agent) or Glycine (Placebo)
Arm/Group Description:	One participant completed the study and one participant started the 1st treatment phase, but was withdrawn during the first treatment phase, hence the primary outcome could not be measured and analyzed.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

2. Secondary Outcome

Title	Does Oral Glutamine Reduce the Number of Clinical Recurrences of Herpes Labialis With or Without PCR Confirmation?
Description	During all phases of the study, participants returned to clinic whenever they had a herpes labialis outbreak for staff to assess, obtain a viral swab and document. If unable to return to clinic in the time frame specified in the protocol, participants would take a photo and obtain a swab of the lesion. The number of recurrences would be documented during each phase of the study.
Time Frame	The screening phase time frame was 4 months. Treatment phase 1 was 5 months. Washout phase was 2 weeks. Treatment phase 2 was 5 months.

Outcome Measure Data

Analysis Population Description

One participant completed the study and one participant started the 1st treatment phase, but was withdrawn during the first treatment phase, hence the secondary outcomes could not be measured and analyzed.

Arm/Group Title	Glutamine (Study Agent) or Glycine (Placebo)
Arm/Group Description:	One participant completed the study and one participant started the 1st treatment phase, but was withdrawn during the first treatment phase, hence the secondary outcomes could not be measured and analyzed.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

3. Secondary Outcome

Title	Does Oral Glutamine Reduce the Time to First Recurrence of Herpes Labialis Diagnosed by Clinical and Microbiologic Criteria or Diagnosed by Clinical Criteria With or Without PCR Confirmation?
Description	During all phases of the study, participants returned to clinic whenever they had a herpes labialis outbreak for staff to assess, obtain a viral swab and document. If unable to return to clinic in the time frame specified in the protocol, participants would take a photo and obtain a swab of the lesion. The number of recurrences and start and end dates of each recurrence would be documented during each phase of the study.
Time Frame	The screening phase time frame was 4 months. Treatment phase 1 was 5 months. Washout phase was 2 weeks. Treatment phase 2 was 5 months.

Outcome Measure Data

Analysis Population Description

One participant completed the study and one participant started the 1st treatment phase, but was withdrawn during the first treatment phase, hence the secondary outcomes could not be measured and analyzed.

Arm/Group Title	Glutamine (Study Agent) or Glycine (Placebo)
Arm/Group Description:	One participant completed the study and one participant started the 1st treatment phase, but was withdrawn during the first treatment phase, hence the secondary outcomes could not be measured and analyzed.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

4. Secondary Outcome

Title	Does Oral Glutamine Reduce the Duration of Recurrences?
Description	During all phases of the study, participants returned to clinic whenever they had a herpes labialis outbreak for staff to assess, obtain a viral swab and document. If unable to return to clinic in the time frame specified in the protocol, participants would take a photo and obtain a swab of the lesion. The number of recurrences and start and end dates of each recurrence would be documented.
Time Frame	The screening phase time frame was 4 months. Treatment phase 1 was 5 months. Washout phase was 2 weeks. Treatment phase 2 was 5 months.

Outcome Measure Data

Analysis Population Description

One participant completed the study and one participant started the 1st treatment phase, but was withdrawn during the first treatment phase, hence the secondary outcomes could not be measured and analyzed.

Arm/Group Title	Glutamine (Study Agent) or Glycine (Placebo)
Arm/Group Description:	One participant completed the study and one participant started the 1st treatment phase, but was withdrawn during the first treatment phase, hence the secondary outcomes could not be measured and analyzed.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

5. Secondary Outcome

Title	Does Oral Glutamine Reduce the Area of Recurrent Lesions?
Description	During all phases of the study, participants returned to clinic whenever they had a herpes labialis outbreak for staff to assess, obtain a viral swab and document. If unable to return to clinic in the time frame specified in the protocol, participants would take a photo and obtain a swab of the lesion. The number of recurrences, start and end dates of each recurrence and measurement of each lesion during each phase of the study would be documented.
Time Frame	The screening phase time frame was 4 months. Treatment phase 1 was 5 months. Washout phase was 2 weeks. Treatment phase 2 was 5 months.

Outcome Measure Data

Analysis Population Description

One participant completed the study and one participant started the 1st treatment phase, but was withdrawn during the first treatment phase, hence the secondary outcomes could not be measured and analyzed.

Arm/Group Title	Glutamine (Study Agent) or Glycine (Placebo)
Arm/Group Description:	One participant completed the study and one participant started the 1st treatment phase, but was withdrawn during the first treatment phase, hence the secondary outcomes could not be measured and analyzed.
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

Adverse Events

Time Frame	From start of drug to 1 month after the last dose of drug. Serious adverse events (SAEs) and non-serious adverse events (AEs) were followed until resolution or until the AE/SAE has stabilized and no more follow-up is required.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Treatment Phase 1		Washout		Treatment Phase 2
Arm/Group Description	2 participants were eligible for the treatment phase of the study after the screening period. 1 participant completed treatment phase 1 & 2. 1 participant was withdrawn from treatment phase 1 after the investigator decided to place the study on hold.		2 participants were eligible for the treatment phase of the study after the screening period. 1 participant completed treatment phase 1 & 2. 1 participant was withdrawn from treatment phase 1 after the investigator decided to place the study on hold.		2 participants were eligible for the treatment phase of the study after the screening period. 1 participant completed treatment phase 1 & 2. 1 participant was withdrawn from treatment phase 1 after the investigator decided to place the study on hold.
All-Cause Mortality
	Treatment Phase 1		Washout		Treatment Phase 2
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
Serious Adverse Events
	Treatment Phase 1		Washout		Treatment Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0.00%)		0/1 (0.00%)		0/1 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Treatment Phase 1		Washout		Treatment Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100.00%)		1/1 (100.00%)		1/1 (100.00%)
Ear and labyrinth disorders
Ear pain † 1	1/2 (50.00%)	3	0/1 (0.00%)	0	0/1 (0.00%)	0
Gastrointestinal disorders
abdominal pain † 1	1/2 (50.00%)	2	0/1 (0.00%)	0	0/1 (0.00%)	0
Oral dysaesthesia † 1	1/2 (50.00%)	1	0/1 (0.00%)	0	0/1 (0.00%)	0
General disorders
Edema † 1 [1]	0/2 (0.00%)	0	1/1 (100.00%)	1	0/1 (0.00%)	0
Infections and infestations
Sinusitis † 1	1/2 (50.00%)	1	0/1 (0.00%)	0	0/1 (0.00%)	0
Laryngitis † 1	1/2 (50.00%)	1	0/1 (0.00%)	0	0/1 (0.00%)	0
Nasopharyngitis † 1	1/2 (50.00%)	2	0/1 (0.00%)	0	0/1 (0.00%)	0
Rhinitis † 1	1/2 (50.00%)	2	0/1 (0.00%)	0	0/1 (0.00%)	0
Investigations
Hepatic enzyme increased † 1 [2]	0/2 (0.00%)	0	0/1 (0.00%)	0	1/1 (100.00%)	1
Blood lactate dehydrogenase abnormal † 2 [3]	1/2 (50.00%)	1	0/1 (0.00%)	0	0/1 (0.00%)	0
Nervous system disorders
Headache † 1	1/2 (50.00%)	1	0/1 (0.00%)	0	0/1 (0.00%)	0
Tension Headache † 1	1/2 (50.00%)	2	0/1 (0.00%)	0	0/1 (0.00%)	0
Psychiatric disorders
Insomnia † 1	1/2 (50.00%)	2	0/1 (0.00%)	0	0/1 (0.00%)	0
Sleep Disorder † 1 [4]	1/2 (50.00%)	1	0/1 (0.00%)	0	0/1 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Sore throat † 1	2/2 (100.00%)	2	0/1 (0.00%)	0	0/1 (0.00%)	0
Epistaxis † 1	1/2 (50.00%)	1	0/1 (0.00%)	0	0/1 (0.00%)	0
Rhinorrhea 1	1/2 (50.00%)	1	0/1 (0.00%)	0	0/1 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA; 2 Term from vocabulary, NCI CTCAE table; [1] pitting edema to bilateral lower legs and ankles; [2] elevated AST; [3] elevated LDH; [4] bizarre dreams

Limitations and Caveats

The protocol was terminated early due to slow recruitment.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Jeffrey I. Cohen, MD
• Organization: National Institute of Allergy and Infectious Diseases, Laboratory of Infectious Diseases
• Phone: (301) 496-5265
• EMail: jcohen@niaid.nih.gov

Publications:

Anderson PM, Ramsay NK, Shu XO, Rydholm N, Rogosheske J, Nicklow R, Weisdorf DJ, Skubitz KM. Effect of low-dose oral glutamine on painful stomatitis during bone marrow transplantation. Bone Marrow Transplant. 1998 Aug;22(4):339-44.

Aquino VM, Harvey AR, Garvin JH, Godder KT, Nieder ML, Adams RH, Jackson GB, Sandler ES. A double-blind randomized placebo-controlled study of oral glutamine in the prevention of mucositis in children undergoing hematopoietic stem cell transplantation: a pediatric blood and marrow transplant consortium study. Bone Marrow Transplant. 2005 Oct;36(7):611-6.

Baker D, Eisen D. Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind, placebo-controlled studies. Cutis. 2003 Mar;71(3):239-42.

• Responsible Party: Jeffrey Cohen, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT00913692
• Other Study ID Numbers: 090159; 09-I-0159
• First Submitted: June 3, 2009
• First Posted: June 4, 2009
• Results First Submitted: February 29, 2012
• Results First Posted: June 11, 2012
• Last Update Posted: June 11, 2012