Minocycline for Cognitive Decline in Sickle Cell Disease

(MINO-SCD Trial)

Overseen By Kristine A Karkoska, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Cincinnati

Must be taking: Hydroxyurea

Must not be taking: Tetracyclines

Disqualifiers: Other SCD genotypes, Stroke, Autoimmune, others

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 12 months

30 Participants Needed

Trial Summary

What is the purpose of this trial?

Sickle cell disease (SCD) is a common, inherited blood disorder that primarily affects people of African Ancestry. It has a lot of complications including neurological complications. The neurological complications of SCD are particularly devastating and lead to cognitive decline even in the absence of overt brain injury. In such cases, it is thought that inflammation in the brain maybe partly responsible for the cognitive decline. The main reasons for this research study are to see 1) how safe and 2) how well minocycline works to try to stop/reverse cognitive decline in people with SCD. People with SCD are at risk for changes in their brain over time that can cause problems with learning, memory, and attention. Part of the reason for this is inflammation within the brain. Minocycline may be able to stop these brain changes by stopping this brain inflammation. Minocycline is a second-generation tetracycline antibiotic that has been shown to both inhibit neuroinflammation and improve cognitive function in a variety of neurodegenerative and psychiatric disorders but has not yet been studied in SCD. We are proposing here, a pilot double-blinded, randomized controlled trial to examine the tolerability and early efficacy of minocycline in adults with SCD at two dosing regimens (200 mg and 300 mg daily) versus placebo over one year. Participants will undergo a neuropsychological exam using the NIH Toolbox Cognition Battery at both study enrollment and exit (after one year) to assess for changes/stability of cognition. Participants will receive monthly phone calls/text messages to assess for adverse events and will be seen every three months for pill counts and routine laboratory monitoring. The primary outcome will be a comparison of adverse events across the two dosing strategies versus placebo. Early evidence for cognitive benefit will also be assessed from the results of the NIH Toolbox.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on hydroxyurea, you can continue taking it as it is the standard-of-care for sickle cell disease.

What data supports the effectiveness of the drug Minocycline for cognitive decline in sickle cell disease?

Research suggests that Minocycline, known for its anti-inflammatory and neuroprotective properties, could be repurposed to treat cognitive deficits in sickle cell disease by targeting neuroinflammation and abnormal neuroplasticity, which are underlying mechanisms of these deficits. ^{1 2 3 4 5}

Is minocycline generally safe for humans?

Minocycline has been associated with several side effects, including dizziness, skin discoloration, and autoimmune reactions like lupus and hepatitis. While these serious side effects are rare, they can occur, especially with long-term use. It's important for doctors to monitor for these potential issues during treatment. ^{6 7 8 9 10}

How does the drug minocycline differ from other treatments for cognitive decline in sickle cell disease?

Minocycline is unique because it targets neuroinflammation and abnormal neuroplasticity, which are underlying mechanisms of cognitive deficits in sickle cell disease. Its anti-inflammatory and antioxidant properties make it a novel option compared to other treatments that may not address these specific pathways. ^{2 3 4 11 12}

Eligibility Criteria

This trial is for adults over 18 with Sickle Cell Disease (SCD), specifically HbSS and HbS-β0thalassemia genotypes, who are treated at the University of Cincinnati Medical Center's SCD clinic. It includes those on hydroxyurea treatment but excludes other SCD genotypes, history of stroke or neurological disorders, premature birth before 30 weeks, chronic blood transfusion therapy, tetracycline allergy, pregnant or breastfeeding women, and individuals with autoimmune conditions.

Inclusion Criteria

I am taking hydroxyurea for sickle cell disease.

I am over 18 with SCD and am a patient at the University of Cincinnati's SCD clinic.

Exclusion Criteria

I have had a stroke or another neurological disorder.

I have sickle cell disease but not the SS genotype.

Premature birth before 30 weeks gestation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either 200 mg or 300 mg of minocycline daily or placebo for 12 months

12 months

Monthly phone calls/text messages, in-person visits every 3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Minocycline

Trial Overview The study tests minocycline's safety and effectiveness in reducing brain inflammation and cognitive decline in people with SCD. Participants will be randomly assigned to receive either minocycline at two different doses (200 mg or 300 mg daily) or a placebo for one year. Their cognitive function will be assessed using the NIH Toolbox Cognition Battery at the start and end of the study.

Participant Groups

Group I: Treatment arm (1) Experimental Treatment 1 Intervention

This arm will receive 200mg of minocycline in a single capsule per day.

Group II: Treatment arm (2) Active Control 1 Intervention

This arm will receive 300 mg of minocycline in a single capsule per day. This capsule is identical in size and appearance as the 200 mg capsule

Group III: Placebo Placebo Group 1 Intervention

This arm will receive the placebo which is similar in size and appearance as the 200 mg and 300 mg capsules.

Minocycline is already approved in United States, European Union, Japan, India for the following indications:

Approved in United States as Minocin for:

• Acne
• Bacterial infections
• Periodontal disease
• Rosacea

Approved in European Union as Minostad for:

• Acne

Approved in Japan as Minopen for:

• Bacterial infections

Approved in India as Minoz for:

• Bacterial infections

Approved in United States as Amzeeq for:

• Acne

Approved in United States as Zilxi for:

• Rosacea

Who Is Running the Clinical Trial?

University of Cincinnati

Lead Sponsor

Trials

442

Recruited

639,000+

References

1. England pubmed.ncbi.nlm.nih.gov

An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Randomized trial of minocycline in the treatment of HIV-associated cognitive impairment. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Role of age and neuroinflammation in the mechanism of cognitive deficits in sickle cell disease. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Minocycline reverses diabetes-associated cognitive impairment in rats. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Minocycline. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Minocycline-induced dermatomyositis. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Vestibular reactions associated with minocycline. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

[Side effects of minocycline in the treatment of acne vulgaris]. [2013]

9. England pubmed.ncbi.nlm.nih.gov

Evaluating FMX-101 as a promising therapeutic for the treatment of acne. [2022]

10. France pubmed.ncbi.nlm.nih.gov

[Minocycline]. [2013]

11. United States pubmed.ncbi.nlm.nih.gov

Neuroprotective effect of minocycline on cognitive impairments induced by transient cerebral ischemia/reperfusion through its anti-inflammatory and anti-oxidant properties in male rat. [2018]

12. England pubmed.ncbi.nlm.nih.gov

High doses of minocycline may induce delayed activation of microglia in aged rats and thus cannot prevent postoperative cognitive dysfunction. [2020]