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A Pilot Pediatric/Adult Study of Gene Expression Profiling and Clinical Characterization of Phototoxicity


N/A
8 Years
N/A
Not Enrolling
Both
Healthy Volunteers, Phototoxicity, Skin Phototype II

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Trial Information

A Pilot Pediatric/Adult Study of Gene Expression Profiling and Clinical Characterization of Phototoxicity


Background:

- Phototoxicity is a sunburn-like response associated with certain medications and is a
phenomenon which is not completely understood. Although clinically similar to a typical
sunburn reaction, the gene expression changes in phototoxic skin reactions may differ
from those in typical sunburn.

- Doxycycline is a relatively well-tolerated and known phototoxic antimicrobial which can
be used in healthy volunteers to increase susceptibility to phototoxicity.

- Characterizing potential risk factors to phototoxicity secondary to voriconazole, a
broad-spectrum antifungal agent associated with potentially treatment-limiting
phototoxicity, may allow identification of subjects at risk for the adverse reaction
via pharmacogenetic evaluation and medical record review.

- Subjects at risk of phototoxicity may benefit from application of effective sunscreens.

Objectives:

- (Primary) To determine the global gene expression profiles in skin exhibiting
phototoxic reactions in healthy volunteers treated with doxycycline, and compare
expression profiles in skin exposed to ultraviolet (UV) radiation occurring in the
absence of doxycycline.

- To investigate the effects of the doxycycline alone in the skin of phototoxic and
non-phototoxic healthy volunteers.

- (Primary) To characterize voriconazole-related phototoxicity reactions in subjects with
the use of phototesting and to determine if these subjects may receive reasonable
phototoxic protection from the use of sunblock.

- (Secondary) To determine the relationship (if any) between voriconazole phototoxicity
and pharmacogenomics (cytochrome P450 isoenzyme CYP2C19).

- (Secondary) To determine the role of UVA and visible light in phototoxicity reactions
associated with doxycycline and voriconazole.

Eligibility:

- I & II) Healthy volunteers with skin phototype II.

- III) Subjects scheduled to begin voriconazole therapy.

- IV) Subjects on chronic voriconazole with or without a history of phototoxicity
reaction.

- Previously treated healthy volunteers (I & II) who were evaluated to be either
phototoxic

OR non-phototoxic.

Design:

- I) For the Screening visit arm, forty healthy volunteers will undergo screening with
pertinent skin exam and blood work to evaluate ANA/ENA and liver function profile.

- II) For the Study visit arm, eligible healthy volunteers will undergo phototesting and
will have skin biopsies prior to initiating a 3-day course of oral doxycycline 100 mg
twice daily.

- After the last dose of doxycycline, healthy volunteers will undergo on-treatment MED
testing.

- In those demonstrating phototoxicity, skin biopsies will be performed and submitted for
processing for microarray analysis.

- III) Thirty-five subjects scheduled to begin voriconazole will undergo CYP450
genotyping and baseline phototesting prior to initiation of voriconazole.

- Adult subjects will be invited to undergo optional skin biopsies pre-drug and on-drug.

- Repeat phototesting will be performed in subjects after at least 7 days of voriconazole
to determine if voriconazole predisposes to phototoxicity.

- Subjects with voriconazole phototoxicity will be invited to undergo sunscreen testing.

- IV) Seventy subjects with prior clinical history of voriconazole phototoxicity as well
as known voriconazole phototoxicity non-reactors will undergo CYP450 genotyping and
potential phototesting.

- To investigate the effects of the doxycycline alone in the skin of healthy volunteers
previously categorized as phototoxic and non-phototoxic

Inclusion Criteria


- INCLUSION CRITERIA:

Subjects who are scheduled to begin voriconazole

1. Subjects with any skin phototype who are scheduled to begin voriconazole therapy.

2. Availability of unexposed skin for testing. Test sites for ssUVR, UVA, and visible
light exposures should be devoid of sunburn, suntan, scars, active dermal lesions,
prior radiotherapy exposure, and uneven skin tones. The presence of nevi will be
acceptable if in the physician's judgment they will not interfere with the study
results. (Excess hair is acceptable if clipped or shaved.)

3. Ages greater than or equal to 8 years old.

4. Ability to participate fully and comply with the procedures of the protocol in the
opinion of the investigator.

5. Ability of subjects or guardians to understand and sign the consent form. Children
must give assent for participation in addition to parental consent.

OR

Subjects currently on or previously on chronic voriconazole

1. Subjects with any skin phototype who have received or are currently receiving chronic
voriconazole therapy.

2. Ages greater than or equal to 8 years old.

3. Ability to participate fully and comply with the procedures of the protocol in the
opinion of the investigator.

4. Ability of subjects or guardians to understand and sign the consent form. Children
must give assent for participation in addition to parental consent.

OR

Healthy volunteers

I) Screening visit arm.

1. Healthy adults aged 18-45 years old of skin phototype II (age and skin phototype
limits selected to simulate subjects evaluated in protocol 04-C-0120).

2. No history of allergy to tetracyclines.

3. No systemic medications, herbal supplements or vitamins that are known to be
associated with abnormal light response or effect on cytochrome P450 enzymes taken
concurrently or within 7 days or 7 half-lives (whichever is longer) of phototesting.

4. No history of liver disease or hepatitis.

5. Willing to undergo screening dermatologic examination and bloodwork.

6. Ability to understand and sign the consent form.

II) Study visit arm

1. Anti-nuclear antibodies (ANA) less than 3 EU; Negative extractable nuclear antigen
(ENA); and negative history of idiopathic abnormal response to sunlight, such as
polymorphic light eruption or solar urticaria. Prior remote history of phototoxicity
reactions acceptable.

2. Availability of unexposed skin for testing. Test sites for ssUVR, UVA, and visible
light exposures should be devoid of sunburn, suntan, scars, active dermal lesions,
prior radiotherapy exposure, and uneven skin tones. The presence of nevi will be
acceptable if in the physician's judgment they will not interfere with the study
results. (Excess hair is acceptable if clipped or shaved.)

3. Liver function profile must be within limits of normal.

4. Ability to participate fully and comply with the procedures of the protocol in the
opinion of the investigator.

EXCLUSION CRITERIA:

Subjects who are scheduled to begin voriconazole

1. Does not meet the inclusion criteria.

2. Extensive skin disease and no testable skin area available.

3. History of allergic reactions to lidocaine for the adults who will undergo the
modified shave biopsy.

4. History of idiopathic abnormal response to sunlight, such as polymorphic light
eruption or solar urticaria. Prior remote history of phototoxicity reaction allowed.

5. Unable to comply with the requirements of the protocol.

6. Any confounding past or present medical illness that in the judgment of the
investigators would pose added risk for study participants (i.e. subjects with
history of graft-versus-host disease; subjects on concurrent chemotherapy or
completed chemotherapy within the preceding two weeks with known photoexacerbating
agents such as alkylating agents, doxorubicin, methotrexate, or cisplatin; or
subjects with previous radiotherapy to the intended sites for phototesting).

7. Pregnancy.

8. History of keloid formation in the adults who will undergo the modified shave biopsy.

OR

Subjects currently on or previously on chronic voriconazole

1. Does not meet the inclusion criteria.

2. Unable to comply with the requirements of the protocol.

3. Any confounding past or present medical illness that in the judgment of the
investigators would pose added risk for study participants.

OR

Healthy volunteers

I) Screening visit arm.

1. Does not meet the Screening visit arm inclusion criteria.

2. History of allergic reactions to lidocaine.

3. Any confounding past or present medical illness that in the judgment of the
investigators would pose added risk for study participants (i.e. subjects with
history of graft-versus-host disease; subjects on concurrent chemotherapy with known
photoexacerbating agents such as alkylating agents, doxorubicin, methotrexate, or
cisplatin; or subjects with previous radiotherapy to the intended sites for
phototesting).

4. Pregnancy.

5. History of keloid formation.

II) Study visit arm

1. Does not meet the Study visit arm inclusion criteria.

2. Extensive skin disease and no testable skin area available.

3. Anti-nuclear antibodies (ANA) greater than or equal to 3 EU or positive extractable
nuclear antigen (ENA); prior history of idiopathic abnormal response to sunlight,
such as polymorphic light eruption or solar urticaria. Prior remote history of
phototoxicity reaction allowed.

4. Unable to comply with the requirements of the protocol.

Type of Study:

Observational

Study Design:

N/A

Principal Investigator

Heidi H Kong, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

060198

NCT ID:

NCT00353158

Start Date:

July 2006

Completion Date:

Related Keywords:

  • Healthy Volunteers
  • Phototoxicity
  • Skin Phototype II
  • Phototesting
  • UVR/UVA
  • Sunburn
  • Doxycycline
  • Voriconazole
  • Phototoxicity
  • Healthy Volunteer
  • HV
  • Dermatitis, Phototoxic

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892