Rituximab + Abatacept for Type 1 Diabetes

(TN25 Trial)

Not currently recruiting at 23 trial locations

Overseen By Michael J Haller, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Must not be taking: Non-insulin glycemic

Disqualifiers: Immune deficiency, Chronic infection, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 10

Duration: 20 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This clinical trial aims to determine if adding the medication Abatacept (an immunosuppressant) to Rituximab (a monoclonal antibody) can better preserve insulin production in people newly diagnosed with Type 1 Diabetes (T1D). Participants will receive either both treatments or Rituximab combined with a placebo (inactive substance). The trial seeks individuals diagnosed with T1D within the past 100 days who have at least one specific type of diabetes-related antibody. Participants must also be willing to engage in intensive diabetes management and continuous glucose monitoring.

As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important advancements in diabetes care.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those using non-insulin drugs that affect blood sugar control within 7 days of screening. It's best to discuss your specific medications with the trial team.

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

Research shows that both rituximab and abatacept have undergone safety studies in people. Previous studies found that abatacept is generally well-tolerated, with most experiencing mild side effects like headaches or colds, which were usually not serious.

Rituximab has also been tested in past studies and can cause some side effects. Common reactions include redness or itching at the infusion site. Some individuals might feel tired or have a mild fever, but these side effects usually don't last long.

Specific data on the safety of using these two treatments together is not available, but each has been tested separately in people. Since this trial is in Phase 2, some evidence suggests the treatment is safe enough for further testing, though more information is still needed. Participants should consult the study team with any concerns or questions about safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike standard treatments for Type 1 Diabetes that typically involve insulin therapy to manage blood sugar levels, rituximab and abatacept offer a novel approach by targeting the immune system directly. Rituximab is unique because it works by depleting B cells, which are part of the immune system that may attack insulin-producing cells in the pancreas. Abatacept, on the other hand, modulates T cell activation, another component of the immune system involved in the autoimmune attack. Researchers are excited about these treatments because they target the underlying immune response in Type 1 Diabetes, potentially slowing or halting disease progression rather than just managing symptoms.

What evidence suggests that this trial's treatments could be effective for Type 1 Diabetes?

Research has shown that rituximab, initially administered to participants in this trial, may help treat type 1 diabetes by preserving insulin production and protecting the pancreas. In previous studies, patients who received rituximab had higher levels of C-peptide, an indicator of insulin production, compared to those who did not receive the treatment. This suggests that rituximab can help maintain insulin production in individuals recently diagnosed with type 1 diabetes.

Regarding abatacept, administered following rituximab in one of the trial arms, studies have found that it can help preserve the function of beta cells, which are crucial for insulin production. Specifically, one study showed that patients treated with abatacept maintained better beta cell function than those who received a placebo. This suggests it might help slow the disease by affecting immune cells that attack insulin-producing cells. Together, these findings support the potential effectiveness of rituximab followed by abatacept in managing type 1 diabetes. ^{1 6 7 8 9}

Who Is on the Research Team?

Kevan Herold, MD

Principal Investigator

Type 1 Diabetes TrialNet Chairman

Daniel Moore, MD

Principal Investigator

Type 1 Diabetes TrialNet

Stephen Gitelman, MD

Principal Investigator

Type 1 Diabetes TrialNet

Are You a Good Fit for This Trial?

This trial is for people aged 8-45 with new onset Type 1 Diabetes who have certain levels of C-peptide, are positive for specific autoantibodies, and meet other health criteria. They must be up to date on vaccinations, not pregnant or planning pregnancy soon, willing to use contraception and follow intensive diabetes management.

Inclusion Criteria

It has been over 4 weeks since I received a live viral vaccine.

My body has antibodies related to diabetes.

I am a man of reproductive age and will use birth control during and for 12 months after rituximab-pvvr treatment.

Exclusion Criteria

I had infectious mononucleosis confirmed by a blood test in the last 3 months.

You have less than 800 white blood cells per microliter of blood.

I have a long-term infection that is not just on my skin.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Rituximab-pvvr is administered by IV infusion over four visits, each one week apart, followed by Abatacept or Placebo subcutaneous injections weekly for 20 months

20 months

4 visits (in-person) for Rituximab, weekly visits for Abatacept/Placebo

Follow-up

Participants are monitored for safety and effectiveness after treatment, including C-peptide response and immune marker analysis

24 months

Regular monitoring every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Abatacept
• Rituximab

Trial Overview

The study compares the effect of Rituximab-pvvr followed by Abatacept versus Rituximab-pvvr alone on C-peptide response in newly diagnosed Type 1 Diabetes patients. It's a double-blinded trial where participants don't know which treatment they're getting.

How Is the Trial Designed?

Group I: Rituximab-pvvr followed by Abatacept Active Control 2 Interventions

Rituximab-pvvr will be given by IV infusion over at least 3 hours, at a dose of 375mg/m2 on four visits each one week apart, starting at Week 0 of the study. Abatacept will be given by a subcutaneous formulation weekly for 20 months, beginning at Week 16 (Month 4) of the study. Dosing will be determined by weight: Up to 25 kg: 50 mg (0.4 mL); 25 to \<50 kg receive 87.5 mg (0.7 mL), and \> 50 kg receive 125 mg (1.0 mL).

Group II: Rituximab-pvvr followed by Placebo Placebo Group 2 Interventions

Rituximab-pvvr will be given by IV infusion over at least 3 hours, at a dose of 375mg/m2 on four visits each one week apart, starting at Week 0 of the study. Placebo will be given by a subcutaneous isotonic saline formulation weekly for 20 months, beginning at Week 16 (Month 4) of the study. Dosing will be match to active comparator, determined by weight: Up to 25 kg: 0.4 mL; 25 to \<50 kg rec 0.7 mL, and \> 50 kg receive 1.0 mL.

Abatacept is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis
• Psoriatic arthritis

Approved in United States as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis
• Psoriatic arthritis

Approved in Canada as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis

Approved in Japan as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis

Who Is Running the Clinical Trial?

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Lead Sponsor

Trials

2,513

Recruited

4,366,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Juvenile Diabetes Research Foundation

Collaborator

Trials

237

Recruited

142,000+

Published Research Related to This Trial

In a clinical trial involving 36 pediatric patients with recent-onset type 1 diabetes, the combination therapy of autologous T regulatory cells (Tregs) and rituximab was found to be more effective than monotherapy in delaying disease progression, as indicated by improved C-peptide levels at 12 and 24 months.

The combined therapy also resulted in a higher proportion of patients maintaining remission compared to the control group, although adverse events were reported in 80% of patients, primarily in the combined and Tregs-only groups, with no serious complications leading to withdrawal or death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined therapy with CD4+ CD25highCD127- T regulatory cells and anti-CD20 antibody in recent-onset type 1 diabetes is superior to monotherapy: Randomized phase I/II trial. Zieliński, M., Żalińska, M., Iwaszkiewicz-Grześ, D., et al.[2022]

In a study of 81 subjects with recent-onset type 1 diabetes, rituximab treatment significantly delayed the decline of β-cell function, as measured by C-peptide levels, compared to placebo over a follow-up period of 30 months.

Although rituximab slowed the decline in C-peptide levels, it did not fundamentally change the disease's underlying mechanisms, as B-lymphocytes returned to baseline levels by 18 months and overall insulin requirements remained similar between the rituximab and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B-lymphocyte depletion with rituximab and β-cell function: two-year results. Pescovitz, MD., Greenbaum, CJ., Bundy, B., et al.[2021]

Abatacept significantly improves health outcomes in patients with rheumatoid arthritis, showing higher likelihoods of achieving American College of Rheumatology (ACR) response rates compared to placebo and other treatments, based on a meta-analysis of 13 randomized control trials involving 5978 patients.

Patients treated with abatacept experienced fewer adverse events compared to those receiving other biologic disease-modifying anti-rheumatic drugs, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of efficacy and safety of abatacept for rheumatoid arthritis: systematic review and meta-analysis. Mohamed Ahamada, M., Wu, X.[2023]

A new study has developed transgenic NOD mice that express human CD20 on B cells, allowing researchers to test the effects of anti-CD20 therapy, which can deplete B cells.

Using this model, the researchers found that anti-CD20 therapy provides some protection against autoimmune diabetes, suggesting that rituximab could be a promising treatment for type 1 diabetes in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B cell depletion: a novel therapy for autoimmune diabetes? Bour-Jordan, H., Bluestone, JA.[2021]

Rituximab (RTX) was administered to a patient with Graves' disease and type 1 diabetes, resulting in no adverse effects and a significant reduction in thyroid stimulating hormone receptor antibodies (TRAb) after treatment.

The treatment led to improved thyroid function and sustained remission of Graves' disease for over a year, suggesting RTX may be an effective option for managing autoimmune polyglandular syndrome in Japanese patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of thyroid remission using rituximab in a patient with type 3 autoimmune polyglandular syndrome including Graves' disease and type 1 diabetes mellitus: a case report. Kurozumi, A., Okada, Y., Arao, T., et al.[2018]

In a study involving 112 patients with recent-onset type 1 diabetes, abatacept treatment resulted in a 59% higher C-peptide concentration after 2 years compared to placebo, indicating better preservation of β-cell function.

Abatacept was well-tolerated, with few infusion-related adverse events and no significant increase in infections or neutropenia, suggesting it is a safe option for modulating T-cell activity in type 1 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Orban, T., Bundy, B., Becker, DJ., et al.[2021]

In a study involving 46 patients with newly diagnosed type 1 diabetes treated with rituximab, antibody responses to new antigens were significantly reduced during B-lymphocyte depletion, indicating a temporary impairment in the immune response.

Despite the reduced antibody responses during treatment, patients showed a return to normal immune function after B-lymphocyte recovery, suggesting that immunization can still be effective once B cells are restored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of rituximab on human in vivo antibody immune responses. Pescovitz, MD., Torgerson, TR., Ochs, HD., et al.[2021]

In a pooled analysis of 8 clinical trials involving 3173 patients treated with intravenous abatacept for rheumatoid arthritis, the long-term safety profile showed low incidence rates of serious infections and malignancies, consistent with short-term data.

The study found that while some specific types of malignancies had higher incidence rates compared to the general population, overall, the safety of abatacept was reassuring, with no unexpected adverse events and rare autoimmune reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of abatacept administered intravenously in treatment of rheumatoid arthritis: integrated analyses of up to 8 years of treatment from the abatacept clinical trial program. Weinblatt, ME., Moreland, LW., Westhovens, R., et al.[2022]

Abatacept is an effective treatment for rheumatoid arthritis (RA), showing positive results in various clinical trials when used alone or in combination with methotrexate and other therapies.

The safety profile of abatacept is generally favorable, with adverse events similar to other biologics, although there is a higher incidence of severe infections compared to placebo, necessitating further research on long-term effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A novel treatment option in rheumatoid arthritis: abatacept, a selective modulator of T-cell co-stimulation]. Dejaco, C., Duftner, C., Wipfler, E., et al.[2021]

Abatacept and rituximab are both effective biologic drugs for treating rheumatoid arthritis in patients who do not respond well to other treatments, showing clinical efficacy in preventing structural damage and medium-term safety in clinical trials.

Despite their common indication, abatacept and rituximab have different mechanisms of action—abatacept is a fusion molecule while rituximab is a monoclonal antibody—leading to different administration patterns and therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Rituximab and abatacept in rheumatoid arthritis]. Gómez Centeno, T.[2012]

In a clinical trial involving new-onset type 1 diabetes (T1D) patients treated with abatacept, researchers identified distinct immune phenotypes, or 'immunotypes', that influenced disease progression and response to treatment.

A specific 'resistance' immunotype was linked to poor responses to abatacept, characterized by increased activated B cells and altered gene expression, suggesting that understanding these immunotypes could help develop better strategies for achieving long-lasting immune tolerance in T1D.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetes. Linsley, PS., Greenbaum, CJ., Speake, C., et al.[2020]

Abatacept and rituximab have been shown to significantly improve treatment outcomes for rheumatoid arthritis patients who do not respond well to traditional tumor necrosis factor inhibitors, with one-year clinical trial data indicating better efficacy and reduced joint damage compared to placebo.

While both therapies have a safety profile that includes infusion reactions and infections, premedication with corticosteroids can help reduce the risk of infusion reactions associated with rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is the place of recently approved T cell-targeted and B cell-targeted therapies in the treatment of rheumatoid arthritis? Lessons from global clinical trials. Smolen, JS.[2015]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10154649/

Abatacept for Delay of Type 1 Diabetes Progression in Stage ...

Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets ...

2.

trialnet.org

trialnet.org/our-research/completed-studies/abatacept

Abatacept Prevention Study

The group treated with abatacept maintained beta cell function better than the placebo group at 12 months. However, 12 months after treatment ended, beta cell ...

3.

orenciahcp.com

orenciahcp.com/efficacy-data.html

Efficacy Data - ORENCIA® (abatacept)

This study evaluated the clinical efficacy and retention for ORENCIA IV as a first-line biologic at 6 months according to patients' baseline BMI using EULAR ...

4.

diabetesjournals.org

diabetesjournals.org/diabetes/article/74/11/2101/163313/Novel-Approach-for-Assessing-Outcomes-of-Type-1

Novel Approach for Assessing Outcomes of Type 1 Diabetes ...

Using this end point, a favorable metabolic impact of abatacept was found after 12 months of treatment. An analytic approach using a binary ...

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT01773707

NCT01773707 | CTLA4-Ig (Abatacept)for Prevention of ...

The study is a 2-arm, multicenter, 1:1 randomized, placebo controlled clinical trial. All subjects will receive close monitoring for development of AGT or T1DM.

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03929601

NCT03929601 | Rituximab-pvvr and Abatacept vs ...

The study is a two-arm, multicenter, double-blinded clinical trial testing sequential therapy with rituximab-pvvr followed by abatacept versus rituximab-pvvr ...

7.

trialnet.org

trialnet.org/our-research/newly-diagnosed-t1d/t1d-relay

Rituximab-pvvr / Abatacept Newly Diagnosed Study (T1D ...

TrialNet is testing rituximab-pvvr and abatacept, one after the other, to learn if using both treatments extend insulin production in people (ages 8-45)

8.

clinicaltrials.ucsf.edu

clinicaltrials.ucsf.edu/trial/NCT03929601

UCSF Diabetes Trial → Rituximab-pvvr and Abatacept vs ...

The study is a two-arm, multicenter, double-blinded clinical trial testing sequential therapy with rituximab-pvvr followed by abatacept versus rituximab-pvvr ...

9.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5074723/

Efficacy, safety, and tolerability of abatacept in the ...

Multiple clinical trials have revealed consistent benefit with regards to clinical and radiographic efficacy, quality of life, and disability in patients ...