Clinical trial NCT02140164: Study of Oral Minocycline in Treating Bilateral Cystoid Macular Edema Associated With Retinitis Pigmentosa
Official title: Pilot Study to Evaluate Oral Minocycline in the Treatment of Cystoid Macular Edema Associated With Retinitis Pigmentosa
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Retinitis Pigmentosa
Keywords: Cystoid Macular Edema
Minocycline
Microglia
Retinitis Pigmentosa
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: The Emmes Company, LLC
First posted: 2014-05-16
Enrollment: 7
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

- Some people with retinitis pigmentosa (RP) have macular edema (swelling) in the central retina. This can cause decreased central vision. The cause of macular edema is unknown, but may involve inflammation. The drug minocycline might help prevent inflammation and therefore might help treat macular edema and improve central visual function .

Objectives:

- To see if minocycline helps people with RP and macular edema.

Eligibility:

- People 12 years and older with RP who have macular edema in at least on eye.

Design:

* Participants will be screened with medical and eye disease history. They will have an eye exam and blood tests. One eye with macular edema will be the study eye. If both eyes are affected, one will be designated the study eye.
* Participants will visit the clinic at least 9 times over at least 14 months. The first 3 study visits will be monthly, then every 2 months.
* Participants will start taking minocycline after visit 3. They will take 1 pill twice daily for at least 1 year.
* Participants will keep a medicine diary and bring it to each visit with their pill bottle and unused pills.

At each study visit, participants will have some or all of the following tests:

* eye and thyroid exams
* blood and pregnancy tests
* microperimetry: participants will press a button when they see a light on a computer screen
* visual field measurement: participants will look at spots on a white screen to test side vision
* electroretinogram: A person will be dark adapted by sitting in the dark for 30 minutes. After the placement of numbing eye drops, special contact lenses will be placed . The participant will watch flashing lights and recordings will be made.

Detailed description: Objective:

Retinitis pigmentosa (RP) is a broad category of genetically heterogeneous diseases involving progressive visual loss by a constriction of visual field and loss of night vision. In up to one-third of patients, the peripheral vision loss can be compounded by central visual acuity loss from the development of cystic macular changes. While RP is a genetic disease, the etiology of progressive cell death, including that of associated cystoid macular edema (CME), is not completely understood. Inflammatory processes involving the activation of resident immune cells of the retina called microglia have been hypothesized to contribute. Minocycline inhibits the activation of microglia, decreasing the production of inflammatory factors implicated in RP progression. The objective of this study is to investigate the safety and possible efficacy of oral minocycline in participants with CME and RP.

Study Population:

Five participants, ages 12 and older, with unilateral or bilateral CME associated with RP will be enrolled initially. However, up to an additional five participants may be enrolled to replace participants who may withdraw from the study prior to reaching the Month 6 visit.

Design:

This is a pilot, single-center, uncontrolled, open-label, prospective, Phase 1/2 clinical trial to evaluate minocycline as a potential treatment for CME secondary to RP. A pre-treatment phase lasting two months will be instituted prior to investigational product (IP) initiation to assess the anatomical variability of CME as well as variability of other measurable parameters as part of the natural history of the disease. Participants will receive an oral dose of 100 mg (or appropriate weight adjusted pediatric dose) of minocycline twice daily for 12 months. There will be a common termination date, which will take place when the last recruited participant has received 12 months of IP. Participants who were recruited in the earlier part of the study will continue taking IP and be followed every two months until the common termination date. At each visit, participants will have visual acuity measured and will undergo optical coherence tomography (OCT) testing to measure retinal thickness. Measures of central visual field sensitivity full-field electroretinograms (ERG) and microperimetry (MP-1) will also be collected.

Outcome Measures:

The primary outcome is the change in CME based on OCT measurements in the study eye at 6 months compared to pre-treatment values. Secondary outcomes include changes in OCT thickness, changes in amplitude of photopic and scotopic responses on ERG testing, changes in microperimetry, and changes in visual field as measured by HVF 30-2 visual field testing at 6 months and 12 months compared to pre-treatment values, as well as CME changes on OCT at 12 months compared to pre-treatment values. Pre-treatment measurements will be analyzed to measure the natural variability of the CME as well as to measure the variability of the functional testing. Safety outcomes will include the number and severity of adverse events (AEs). Ocular safety outcomes will be indicated by changes in visual acuity, ocular surface changes, intraocular inflammation and any other ocular changes not consistent with the natural progression of RP.

Eligibility criteria: * INCLUSION CRITERIA:
* To be eligible, the following inclusion criteria must be met, where applicable.
* Participant must be 12 years of age or older.
* Participant (or legal guardian) must understand and sign the protocol's informed consent document.
* Participant must have evidence of retinitis pigmentosa (RP) as defined by characteristic electroretinogram (ERG) responses and visual fields.
* Participant must be able to swallow pills.
* Participant must have normal renal function and liver function or have mild abnormalities not above grade 1 as defined by the Common Terminology Criteria for Adverse Events v4.0 (CTCAE).
* Participant must agree to minimize exposure to sunlight or artificial ultraviolet (UV) rays and to wear protective clothing, sunglasses and sunscreen \[minimum sun protection factor (SPF) 15\] if s/he must be out in the sun.
* Any female participant of childbearing potential must have a negative pregnancy test at screening and be willing to undergo pregnancy tests throughout the study.
* Any female participant of childbearing potential and any male participant able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must agree to practice two acceptable methods of contraception throughout the course of the study and for at least one week after investigational product (IP) discontinuation. Acceptable methods of contraception include:

  * hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring),
  * intrauterine device,
  * barrier methods (diaphragm, condom) with spermicide, or
  * surgical sterilization (hysterectomy or tubal ligation).

EXCLUSION CRITERIA:

A participant is not eligible if any of the following exclusion criteria are present.

* Participant is actively receiving study therapy in another investigational study.
* Participant is started on (or changed dosage of) topical or systemic carbonic anhydrase inhibitor (CAI) treatment in the 3 months prior to enrollment.
* Participant is actively receiving systemic steroids or has received systemic steroids in the 3 months prior to enrollment.
* Any female participant of childbearing potential that is pregnant, breast-feeding or planning to become pregnant during the study.
* Participant is expected to be unable to comply with study procedures or follow-up visits.
* Participant has evidence of an ocular disease other than RP in either eye that may confound the outcome of the study (e.g., diabetic retinopathy with 10 or more hemorrhages or microaneurysms, uveitis, pseudovitelliform macular degeneration, severe myopia).
* Participant is on ocular or systemic medications known to be toxic to the lens, retina or optic nerve (e.g., ethambutol, chloroquine, or hydroxychloroquine).
* Participant has a condition that would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control) by interfering with the participant s ability to engage in the required protocol evaluation and testing and/or comply with study visits.
* Participant has a history of chronic renal failure requiring dialysis or kidney transplant.
* Participant has a history of chronic hepatitis or liver failure.
* Participant has a history of thyroid cancer.
* Participant has an allergy or hypersensitivity to minocycline or any drug in the tetracycline family.
* Participant is currently taking a tetracycline medication.
* Participant is taking any medication that could adversely interact with minocycline such as methoxyflurane.
* Participant has a prior history of idiopathic intracranial hypertension.

Primary outcomes:
measure: Change in Cystoid Macular Edema (CME) Based on Optical Coherence Tomography (OCT) Measurements in the Study Eye at 6 Months Compared to the Average of the Pre-treatment Values.
timeFrame: Pre-treatment and 6 Months
Secondary outcomes:
measure: Change in Cystoid Macular Edema (CME) Based on Optical Coherence Tomography (OCT) Measurements in the Study Eye at 12 Months Compared to the Average of the Pre-treatment Values
timeFrame: Pre-treatment and 12 Months
measure: Changes in Amplitude of Photopic and Scotopic Responses on Electroretinogram (ERG) Testing at 6 Months as Compared to the Average of Pre-treatment Values
timeFrame: Pre-Treatment and 6 Months
measure: Changes in Amplitude of Photopic and Scotopic Responses on Electroretinogram (ERG) Testing at 12 Months as Compared to the Average of Pre-treatment Values
timeFrame: Pre-treatment and 12 Months
measure: Change in Microperimetry at 6 Months as Compared to the Average of Pre-treatment Values
timeFrame: Pre-treatment and 6 Months
measure: Change in Microperimetry at 12 Months as Compared to the Average of Pre-treatment Values
timeFrame: Pre-treatment and 12 Months
measure: Change in Visual Field as Measured by HVF 30-2 Visual Field Testing at 6 Months as Compared to the Average of Pre-treatment Values
timeFrame: Pre-treatment and 6 Months
measure: Change in Visual Field as Measured by HVF 30-2 Visual Field Testing at 12 Months as Compared to the Average of Pre-treatment Values
timeFrame: Pre-treatment and 12 Months
measure: Number of Study Eyes Achieving a 15-letter or More Worsening in Electronic Visual Acuity (EVA) at 12 Months as Compared to Baseline
timeFrame: Baseline and 12 Months
measure: Number of Ocular Adverse Events
timeFrame: Study Duration, up to 16 Months
measure: Number of Non-ocular Adverse Events
timeFrame: Study Duration, up to 16 Months
measure: Number of Severe Adverse Events
timeFrame: Study Duration, up to 16 Months
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Eye Institute (NEI)
name: Catherine A Cukras, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Li ZY, Possin DE, Milam AH. Histopathology of bone spicule pigmentation in retinitis pigmentosa. Ophthalmology. 1995 May;102(5):805-16. doi: 10.1016/s0161-6420(95)30953-0.
citation: Chang GQ, Hao Y, Wong F. Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron. 1993 Oct;11(4):595-605. doi: 10.1016/0896-6273(93)90072-y.
citation: Dave AD, Chen KG, Chiang TT, Singaravelu J, Alvarez JA, Wong WT, Cukras CA. Oral minocycline for the treatment of retinitis pigmentosa-associated cystoid macular edema: results of a phase I/II clinical trial. Graefes Arch Clin Exp Ophthalmol. 2023 Aug;261(8):2209-2220. doi: 10.1007/s00417-023-05986-6. Epub 2023 Mar 8.