Minocycline In Neurocognitive Outcomes - Sickle Cell Disease

Study Overview: This is a pilot study examining tolerability of low (200 mg daily) and high (300 mg daily) oral minocycline in adults with SCD compared to placebo. We will aim to enroll and randomize 30 adults with SCD and monitor for 12 months. Preliminary data regarding cognition will be obtained at baseline and 12 months, safety/laboratory monitoring will be incorporated into clinical care at 3 month intervals, with monthly phone calls and/or text messaging to inquire about any adverse event that may have occurred since the last clinic visit.

Inclusion/Exclusion: Adults (age ≥ 18 years old) with SCD (HbSS and HbS-β0thalassemia genotypes only) who are followed at the University of Cincinnati Medical Center's SCD clinic are eligible to participate. As hydroxyurea is the standard-of-care in SCD, individuals on hydroxyurea will be included. The exclusion criteria are as follows: 1) adults with other SCD genotypes (HbSC or HbS- β+thalassemia), 2) individuals with a history of overt stroke or other known neurological disorder, 3) premature birth before 30 weeks gestation, 4) monthly therapy with chronic blood transfusions, 5) coexisting autoimmune condition due to an elevated risk for autoimmune-related complications with tetracyclines, and 6) tetracycline allergy. Study members will approach eligible individuals at their regularly scheduled hematology visits to assess for interest and complete consent. All study-related procedures will be performed by the University of Cincinnati's specifications.

Dose Justification: The proposed dosing is based on previous double-blind placebo-controlled studies of minocycline use in neuropsychiatric disorders. In the Minocycline in Alzheimer Disease Efficacy (MADE) trial 200 mg daily resulted in no difference in adverse event or drug discontinuation rates compared to placebo, in contrast to 400 mg daily, which had significantly higher rates of dermatologic and gastrointestinal side effects.22 In patients with schizophrenia, minocycline 200 mg daily was associated with improvement in cognition at 3 months compared to placebo with no difference in adverse events.19, 38 A larger study of 204 patients with schizophrenia receiving minocycline 300 mg daily found no difference in adverse events between the minocycline and placebo groups.21 Finally, patients with clinical isolated syndrome (a precursor to multiple sclerosis) who received minocycline 200 mg daily saw a decrease in conversion to multiple sclerosis at six months; however, the rates of trial withdrawal and adverse events, including rash, dizziness, and dental discoloration, were higher in the minocycline versus placebo arm.39 Thus, it is unclear whether 200 mg daily or 300 mg daily is the optimal dose in adult SCD.

Cognitive Assessments: Participants will complete the NIH Toolbox: Cognition Battery, the Consortium to Establish a Registry for Alzheimer's disease Verbal Learning Test (CERAD-VLT), and the Complex Taylor Figure at baseline visit and 12-month follow up. The NIH Toolbox, a cognitive outcome measure designed for epidemiologic research and clinical trials, is administered via tablet application with automated scoring and was validated in a diverse cohort of 476 participants ages 3-85 years.40 The NIH Toolbox has previously been utilized in pediatric SCD participants, detecting the decreased inhibitory control, processing speed, and cognitive flexibility which have been observed in previous studies.41 To compliment the NIH Toolbox we will utilize the CERAD-VLT to assess verbal learning, including episodic memory.42 Lastly, children with SCD can have significant visual spatial dysfunction as the result of cerebral infarcts, we anticipate the same might be the case with the adults and as such, we will assess visual spatial ability using the Complex Taylor Figure tool.8, 43 Intervention, Measurements, & Data Collection: Upon enrollment, all participants will undergo neuropsychological assessment at baseline using the tools described above. All participants will also undergo a baseline symptom assessment, physical examination, peripheral oxygen saturation, and laboratory analysis, including complete blood count (CBC) with differential, reticulocyte count, complete metabolic panel (CMP), fetal hemoglobin (HbF), thyroid function tests, and spot urine microalbumin. If any laboratory analysis had been completed within two weeks prior to enrollment, this will not be repeated. Individuals will then be randomized to receive minocycline 200 mg daily, minocycline 300 mg daily, or placebo via a random number generator. Both the patient and investigator will be blinded to the enrollment status. Participants will return for pill counts, laboratory examination, and physical exam every three months. Participants will also fill out a standardized assessment regarding their health and any side effects monthly; this will be administered via RedCAP survey either through phone call/text message or via tablet application and can be completed at home during the months between study visits. The study visits will be timed ideally with routine clinical follow ups in the Hoxworth Clinic, but with all study-related procedures taking place in the Schubert Research Clinic at Cincinnati Children's Hospital Medical Center. Participants will also undergo the following labs every three months during study visits: CBC, CMP, reticulocyte count, and HbF; these will not be repeated if obtained clinically within two weeks of the study visit date. Thyroid function tests and urine microalbumin will be collected every six months. Study enrollees will be followed for a period of 12 months from their day of starting either the drug or placebo. Participants will then repeat the components of the baseline studies, including the neuropsychological assessment. Participants and study investigators will have the option to be unblinded to each participant's study arm.

Study Duration: The total study duration will be two years; we expect 6 months for patient recruitment/randomization followed by 12 months of therapy and another 6 months for data analysis/publication.