Multiple Therapies for Down Syndrome Regression Disorder

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Jonathon Santoro, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Colorado, Denver

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

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

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing three treatments for Down Syndrome Regression Disorder (DSRD) in people with Down Syndrome. The treatments include a calming medication, an immune-boosting blood product, and a drug that reduces immune activity. The goal is to see which treatment is safest and most effective for managing severe symptoms.

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.

What data supports the effectiveness of the drug Intravenous Immunoglobulin (IVIG) for treating Down Syndrome Regression Disorder?

Research shows that Intravenous Immunoglobulin (IVIG) has been effective in treating conditions like primary immunodeficiency and Landau-Kleffner syndrome, where it improved symptoms such as speech and behavior. This suggests it might help with similar symptoms in Down Syndrome Regression Disorder. ^{1 2 3 4 5}

Is lorazepam generally safe for use in humans?

Lorazepam is generally considered safe for use in humans, but it can sometimes cause unexpected reactions, such as worsening seizures in some cases. ^{6 7 8 9 10}

How is the drug for Down Syndrome Regression Disorder different from other treatments?

This drug combination is unique because it includes intravenous immunoglobulin (IVIG), which is typically used for immune deficiencies and inflammatory conditions, along with lorazepam, a medication for anxiety, and tofacitinib, a drug that modulates the immune system. This combination targets both immune and behavioral aspects of the disorder, which is not common in standard treatments. ^{1 11 12 13 14}

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

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Intravenous immunoglobulin (IVIG) (Immunomodulator)
• Lorazepam (Benzodiazepine)
• Tofacitinib (Janus kinase (JAK) inhibitor)

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.

Participant Groups

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 Canada for the following indications:

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+

Aviva Abosch

University of Colorado, Denver

Chief Medical Officer since 2019

MD

Uday B. Kompella

University of Colorado, Denver

Chief Executive Officer since 2015

PhD in Pharmaceutical Sciences

Children's Hospital Los Angeles

Collaborator

Trials

257

Recruited

5,075,000+

Paul S. Viviano

Children's Hospital Los Angeles

Chief Executive Officer since 2015

Master of Public Health from UCLA Fielding School of Public Health

Alan S. Wayne

Children's Hospital Los Angeles

Chief Medical Officer since 2023

MD

Findings from Research

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 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 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 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]

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]

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]

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 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]

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]

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 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]

References

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

Efficacy and safety of human intravenous immunoglobulin 5% (Ig VENA) in pediatric patients affected by primary immunodeficiency. [2021]

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

Efficacy of intravenous immunoglobulin in Landau-Kleffner syndrome. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Outcomes of ICU patients treated with intravenous immunoglobulin for sepsis or autoimmune diseases. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

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

5. Austria pubmed.ncbi.nlm.nih.gov

[Intravenous immunoglobulin in the treatment of malignant epilepsy in children]. [2006]

6. England pubmed.ncbi.nlm.nih.gov

Lorazepam v. diazepam for pediatric status epilepticus. [2017]

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

A cost analysis of enterally administered lorazepam in the pediatric intensive care unit. [2019]

8. United States 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. [2020]

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

Paradoxical precipitation of tonic seizures by lorazepam in a child with atypical absence seizures. [2019]

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

[Use of injectable lorazepam in status epilepticus: a comparative study in French-speaking hospitals]. [2015]

11. England pubmed.ncbi.nlm.nih.gov

Behavior abnormality following intravenous immunoglobulin treatment in patients with primary antibody deficiencies. [2010]

12. Korea (South) pubmed.ncbi.nlm.nih.gov

Clinical Outcomes of Low-Dose Methotrexate Therapy as a Second-Line Drug for Intravenous Immunoglobulin-Resistant Kawasaki Disease. [2018]

13. Netherlands 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. [2020]

14. Switzerland 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. [2023]