Multiple Therapies for Down Syndrome Regression Disorder

Recruiting at 1 trial location

Overseen By Belinda Enriquez Estrada, MS

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Must not be taking: Immunosuppressants, Biologics, Chemotherapeutics, others

Disqualifiers: Genetic disorder, Cardiac disease, Viral infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

66 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines treatments for Down Syndrome Regression Disorder (DSRD), a condition causing sudden and severe changes in individuals with Down syndrome, such as catatonia, hallucinations, and aggression. The study evaluates the safety and effectiveness of three treatments: lorazepam, intravenous immunoglobulin (IVIG), and tofacitinib. Participants will be randomly assigned to one of these treatments to determine which is most effective. Suitable candidates have Down syndrome and exhibit DSRD symptoms, including sudden behavioral changes or loss of daily skills. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any medications that are meant to treat symptoms of Down Syndrome Regression Disorder or that might interfere with the study treatments. There is a 'washout period' required for certain medications, meaning you must stop taking them for a specific time before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that lorazepam is generally safe for short-term use and is approved for treating anxiety. Some individuals might experience sleepiness or confusion, but most manage these effects well.

Studies have found that tofacitinib can assist with immune issues common in Down syndrome. It has been used safely for other conditions, though mild side effects like headaches may occur.

For intravenous immunoglobulin (IVIG), research indicates it is safe for individuals with Down Syndrome Regression Disorder (DSRD). Most tolerate it well, though some reactions can occur.

Each of these treatments is usually well-tolerated. Most side effects are mild, but discussing any concerns with a doctor is always advisable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Down Syndrome Regression Disorder because they offer new approaches compared to current options. Intravenous immunoglobulin (IVIG) boosts the immune system in a unique way by providing antibodies directly, which is different from typical anti-inflammatory drugs. Lorazepam targets anxiety and agitation through its calming effects on the nervous system, which can help manage mood symptoms that are not the primary focus of existing therapies. Tofacitinib, an oral pill, works by inhibiting Janus kinase enzymes, a mechanism that could reduce inflammation more effectively than standard treatments. These diverse mechanisms offer hope for addressing the complex symptoms of this condition in novel ways.

What evidence suggests that this trial's treatments could be effective for Down Syndrome Regression Disorder?

This trial will compare multiple therapies for Down Syndrome Regression Disorder (DSRD). Research has shown that these treatments work differently for different people. Participants in this trial may receive Lorazepam, a drug often used to treat anxiety, which has produced mixed results. Some patients experience slight improvements in skills like speaking and writing, while others notice little change.

Another treatment option in this trial is Tofacitinib, a drug that blocks certain enzymes. It has improved symptoms in a few DSRD cases. While it may not fully stop the immune system's response, it can reduce some immune activity markers in people with Down syndrome.

Participants may also receive Intravenous immunoglobulin (IVIG), which has shown promise in reversing DSRD symptoms. Several studies have found IVIG to be safe and effective for treating this condition, offering hope for children and young adults with DSRD. ^{3 6 7 8 9}

Who Is on the Research Team?

Joaquin Espinosa, PhD

Principal Investigator

Linda Crnic Institute for Down Syndrome

Elise Sannar, MD

Principal Investigator

Children's Hospital Colorado

Jonathon Santoro, MD

Principal Investigator

Children's Hospital Los Angeles

Are You a Good Fit for This Trial?

This trial is for individuals aged 8-30 with Down Syndrome who may have Down Syndrome Regression Disorder (DSRD), which includes symptoms like catatonia and hallucinations. Participants must not be on certain medications, have specific health conditions like heart disease or severe infections, or a history of allergies to the study drugs.

Inclusion Criteria

I am between 8 and 30 years old and have Down syndrome.

Must agree to random treatment assignment.

I agree to stop taking certain medications for my condition during the study.

Exclusion Criteria

My tests show I have antibodies in my brain that could cause inflammation.

I have not treated my underactive or overactive thyroid.

You are allergic or have bad reactions to lorazepam, IVIG, or tofacitinib.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Observational

A subset of participants undergo an initial observational period

12 weeks

Treatment

Participants receive one of three therapies: lorazepam, IVIG, or tofacitinib for 12 weeks

12 weeks

Regular visits for monitoring and administration

Titration

Participants on lorazepam receive titration doses for an additional period

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Intravenous immunoglobulin (IVIG)
• Lorazepam
• Tofacitinib

Trial Overview The trial tests the safety and effectiveness of lorazepam, intravenous immunoglobulin (IVIG), and tofacitinib in treating DSRD. Patients will be randomly assigned one of these treatments and monitored for their response.

How Is the Trial Designed?

Group I: Tofacitinib Experimental Treatment 1 Intervention

Tofacitinib will be administered as an oral pill at 5 mg twice daily over the 12-week study.

Group II: Lorazepam Experimental Treatment 1 Intervention

Participants will receive lorazepam as an oral pill three times daily for 12 weeks as well as titration doses for an additional 4 weeks (approximately).

Group III: Intravenous immunoglobulin (IVIG) Experimental Treatment 1 Intervention

Participants will receive 4 doses of IVIG treatment over 12 weeks.

Intravenous immunoglobulin (IVIG) is already approved in United States, European Union, Canada for the following indications:

Approved in United States as IVIG for:

• Primary immunodeficiency diseases
• Chronic inflammatory demyelinating polyneuropathy (CIDP)
• Multifocal motor neuropathy
• Kawasaki disease
• Immune thrombocytopenic purpura (ITP)
• Autoimmune hemolytic anemia
• Neonatal alloimmune thrombocytopenia
• Down Syndrome Regression Disorder (off-label)

Approved in European Union as IVIG for:

• Primary immunodeficiency diseases
• Chronic inflammatory demyelinating polyneuropathy (CIDP)
• Multifocal motor neuropathy
• Kawasaki disease
• Immune thrombocytopenic purpura (ITP)
• Autoimmune hemolytic anemia
• Neonatal alloimmune thrombocytopenia

Approved in Canada as IVIG for:

• Primary immunodeficiency diseases
• Chronic inflammatory demyelinating polyneuropathy (CIDP)
• Multifocal motor neuropathy
• Kawasaki disease
• Immune thrombocytopenic purpura (ITP)
• Autoimmune hemolytic anemia
• Neonatal alloimmune thrombocytopenia

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Children's Hospital Los Angeles

Collaborator

Trials

257

Recruited

5,075,000+

Published Research Related to This Trial

The use of intravenous immunoglobulins (IVIG) in pediatric patients increased by 30.2% from 2007 to 2014, with over 53,648 unique patients treated for more than 2300 primary diagnoses, indicating a growing reliance on IVIG for various conditions.

IVIG was frequently used off-label, particularly for conditions like Kawasaki disease and idiopathic thrombocytopenic purpura, suggesting its role in treating diseases with abnormal immune responses, but more research is needed to evaluate the effectiveness and cost-efficiency of these off-label uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changing trends in IVIG use in pediatric patients: A retrospective review of practices in a network of major USA pediatric hospitals. Balch, A., Wilkes, J., Thorell, E., et al.[2020]

In a study of five patients with primary antibody deficiencies receiving intravenous immunoglobulin (IVIG) therapy, some experienced behavioral disorders, including increased hyperactivity after treatment.

Before IVIG administration, four patients showed mild hyperactivity, but after treatment, three patients' hyperactivity worsened, indicating a potential link between IVIG therapy and behavioral changes that requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Behavior abnormality following intravenous immunoglobulin treatment in patients with primary antibody deficiencies. Saroukhani, S., Aghamohammadi, A., Mahmoudi-Gharaei, J., et al.[2010]

Kedrion 5% intravenous immunoglobulin G (IVIg) treatment is both effective and safe for children and adolescents with primary immunodeficiencies, helping to reduce their susceptibility to severe infections.

The study included a long follow-up period totaling 71 patient-years, making it one of the few to specifically evaluate the safety and efficacy of IVIg in a pediatric population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of human intravenous immunoglobulin 5% (Ig VENA) in pediatric patients affected by primary immunodeficiency. Ricci, S., Lippi, F., Canessa, C., et al.[2021]

In a study involving 59 children under 12 years old with primary immunodeficiency diseases or immune thrombocytopenia, Clairyg® 50 mg/mL was found to be well tolerated, with most reported adverse events being mild or moderate, such as headache and vomiting.

Clairyg® effectively controlled serious bacterial infections in patients with primary immunodeficiency and managed bleeding episodes in those with immune thrombocytopenia, demonstrating its safety and efficacy in real-life conditions without new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with CLAIRYG® 50 mg/mL (intravenous immunoglobulin) in children under 12 years with primary immunodeficiency or immmune thrombocytopenia: a post-approval safety study. Mahlaoui, N., Fouyssac, F., Mazingue, F., et al.[2023]

In a study of 111 ICU patients, those with sepsis who received high-dose intravenous immunoglobulin (IVIg) showed improved outcomes, including shorter ICU stays and reduced mortality rates.

Conversely, patients with autoimmune diseases did not benefit from IVIg treatment, likely due to receiving it later in their hospital stay compared to the sepsis group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of ICU patients treated with intravenous immunoglobulin for sepsis or autoimmune diseases. Tocut, M., Kolitz, T., Shovman, O., et al.[2022]

In a study involving five patients with Landau-Kleffner syndrome, administering 2 gm/kg of intravenous gamma globulin (IVIG) over 4 days resulted in a significant reduction in severity scores related to speech, comprehension, behavior, seizures, and EEG activity (P = 0.025).

Two of the patients experienced a dramatic response, achieving complete resolution of their symptoms, indicating that IVIG may be an effective treatment option for this syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of intravenous immunoglobulin in Landau-Kleffner syndrome. Mikati, MA., Saab, R., Fayad, MN., et al.[2019]

In a study involving 488 patients with various antibody deficiencies, intravenous immunoglobulin (IVIG) Intratect demonstrated high effectiveness and patient satisfaction, with over 92% of physicians reporting very good outcomes.

The treatment improved IgG trough levels significantly, with only 22% of patients having inadequate levels after three infusions, and adverse reactions were low at 3% per infusion, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefits of immunoglobulin substitution in primary and secondary immunodeficiencies: Interim analysis of a prospective, long-term non-interventional study. Bauhofer, A., Schimo, S., Klausmann, M.[2021]

A 10-year-old girl with Lennox-Gastaut syndrome experienced an increase in tonic seizures after receiving intravenous lorazepam, indicating a paradoxical reaction to the medication.

The report highlights that benzodiazepines, typically used to control seizures, can sometimes lead to paradoxical seizure exacerbation in certain patients, suggesting the need for careful monitoring when prescribing these drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paradoxical precipitation of tonic seizures by lorazepam in a child with atypical absence seizures. DiMario, FJ., Clancy, RR.[2019]

In a study of 15 children with malignant epilepsy who did not respond to standard treatments, 10 showed a significant reduction or complete absence of seizures after 6 months of intravenous immunoglobulin therapy.

The therapy was particularly effective in children with IgG2 subclass deficiency, suggesting that intravenous immunoglobulin could be a promising treatment option for certain cases of malignant epilepsy, although more research is needed due to the small sample size.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Intravenous immunoglobulin in the treatment of malignant epilepsy in children]. Sterio, M., Gebauer, E., Vucicević, G., et al.[2006]

A randomized clinical trial compared the efficacy and safety of intravenous lorazepam and diazepam in treating pediatric status epilepticus, aiming to identify which medication is superior.

The study's results will help inform treatment protocols for pediatric patients experiencing prolonged seizures, potentially improving outcomes and safety in emergency settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lorazepam v. diazepam for pediatric status epilepticus. Pinto, RF., Turnbull, J.[2017]

In a survey of 12 hospitals within the Mother-Child French-speaking Network, it was found that injectable lorazepam (IL) is only used in one hospital in France, while it is widely marketed and used in Switzerland, Canada, and Belgium for pediatric status epilepticus.

Although pharmacokinetic data suggest that IL may be preferable to injectable diazepam, there is currently no evidence proving that IL is superior in treating pediatric status epilepticus, highlighting inconsistencies in treatment protocols across different countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Use of injectable lorazepam in status epilepticus: a comparative study in French-speaking hospitals]. Curatolo, N., Prot-Labarthe, S., Auvin, S., et al.[2015]

In a study of 75 patients with IVIG-resistant Kawasaki disease, low-dose methotrexate (MTX) led to significant reductions in fever and inflammation within 24 hours and one week, respectively.

MTX was well-tolerated with no observed adverse effects, suggesting it could be a safe and effective treatment option for patients who do not respond to standard IVIG therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Outcomes of Low-Dose Methotrexate Therapy as a Second-Line Drug for Intravenous Immunoglobulin-Resistant Kawasaki Disease. Jang, H., Kim, KY., Kim, DS.[2018]

Transitioning from intravenous midazolam to enterally administered lorazepam in mechanically ventilated children led to a significant reduction in midazolam usage by approximately 46.7%, allowing for effective sedation maintenance.

This change resulted in substantial cost savings of $42,904 for the hospital, demonstrating that lorazepam is a convenient and effective alternative for long-term sedation in critically ill pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A cost analysis of enterally administered lorazepam in the pediatric intensive care unit. Lugo, RA., Chester, EA., Cash, J., et al.[2019]

Intranasal midazolam (INM) was found to be as effective as intravenous lorazepam (IVL) for terminating seizures and preventing seizure clusters in adults, based on a retrospective study of 50 patients in an epilepsy monitoring unit.

INM offers the advantage of avoiding the need for intravenous access, making it a practical alternative to IVL for rescue therapy in patients experiencing seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of intranasal midazolam versus intravenous lorazepam for seizure termination and prevention of seizure clusters in the adult epilepsy monitoring unit. Owusu, KA., Dhakar, MB., Bautista, C., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9949176/

Immunotherapy Responsiveness and Risk of Relapse in ... Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause.

2. nature.com nature.com/articles/s41398-023-02579-z

Immunotherapy responsiveness and risk of relapse in ... This study evaluated the clinical effectiveness of IVIg and evaluated clinical characteristics associated with relapse after therapy discontinuation.

3. neurology.org neurology.org/doi/10.1212/WNL.0000000000208381

Safety and Tolerability of Home Infusions in Down ... Multiple studies on DSRD have revealed that immunotherapy with IVIg is both safe and effective although site of infusion has never been studied.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0149291824003710

Safety and Tolerability of Home Infusions in Down ... Multiple studies on DSRD have revealed that immunotherapy with intravenous immunoglobulin (IVIg) is both safe and effective, although site of infusion has never ...

5. pharmacytimes.com pharmacytimes.com/view/ivig-shows-potential-to-reverse-symptoms-of-down-syndrome-regression-disorder

IVIG Shows Potential to Reverse Symptoms of Down ... Treatment with intravenous immunoglobulin (IVIG) shows promise for children and young adults with Down syndrome regression disorder (DSRD), according to ...

6. neurology.org neurology.org/doi/10.1212/WNL.0000000000205288

Safety and Tolerability of Intravenous Immunoglobulin ... This study sought to evaluate the safety and tolerability of IVIg in individuals with DSRD compared to a real-world cohort of individuals with pediatric onset ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38169137/

Safety and tolerability of intravenous immunoglobulin infusion ... This study sought to evaluate the safety and tolerability of IVIg in individuals with DSRD compared to a real-world cohort of individuals with pediatric onset ...

8. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.63524

Safety and tolerability of intravenous immunoglobulin ... Yet the tolerability of infusions in individuals with DS and the safety of IVIg remains unknown in this population. This study sought to ...

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39690018/

Safety and Tolerability of Home Infusions in Down ... Multiple studies on DSRD have revealed that immunotherapy with intravenous immunoglobulin (IVIg) is both safe and effective, although site of infusion has never ...