CELZ-201 for Type 1 Diabetes (CREATE-1 Trial)
Recruiting in Palo Alto (17 mi)
Overseen ByCamillo Ricordi, MD
Age: 18 - 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Creative Medical Technology Holdings Inc
Approved in 1 jurisdiction
Trial Summary
What is the purpose of this trial?This trial is testing CELZ-201, a new treatment for people who have just been diagnosed with Type 1 Diabetes. The treatment is given directly into the bloodstream to help control blood sugar levels.
Will I have to stop taking my current medications?
The trial requires that participants do not use diabetes medications other than insulin and avoid non-insulin drugs that affect blood sugar control within 7 days of screening. If you are on such medications, you may need to stop them before joining the trial.
What data supports the effectiveness of the CELZ-201 treatment for Type 1 Diabetes?
Research on similar treatments, like teplizumab and otelixizumab, shows they can help preserve insulin-producing cells in people with new-onset Type 1 Diabetes. These treatments work by targeting the immune system to protect the cells that make insulin.
12345How is the CELZ-201 treatment different from other treatments for type 1 diabetes?
CELZ-201 (AlloStem) is unique because it potentially involves a novel approach to treating type 1 diabetes by targeting the autoimmune response that destroys insulin-producing cells, unlike traditional treatments that primarily focus on insulin replacement.
678910Eligibility Criteria
Adults aged 18-35 with recent onset Type 1 Diabetes, confirmed by specific autoantibodies and a certain level of C-peptide. Participants must be mentally stable, able to follow the study protocol, manage their diabetes as usual, have good kidney function and venous access for blood draws. Women must not be pregnant or breastfeeding and along with men, agree to use two forms of birth control during the study.Inclusion Criteria
My kidney function is good.
I am between 18 and 35 years old.
I agree to use two approved birth control methods for 2 years.
I have Type 1 Diabetes confirmed by specific autoantibodies.
Exclusion Criteria
I haven't taken immunosuppressives, immunomodulators, or cytotoxic drugs in the last 3 months.
My blood pressure is not higher than 140/90 mmHg.
I do not have liver disease, blood clotting disorders, or take long-term blood thinners (except for low-dose aspirin).
I do not have any current infections like colds, UTIs, or stomach bugs.
I do not have chronic infections like hepatitis, tuberculosis, or HIV.
I am using or plan to use diabetes medications besides insulin.
I have a history of heart disease or significant heart test abnormalities.
I have a history of severe stomach or digestive problems.
I have symptoms of gallstones, pancreatitis, or stomach ulcers.
I have received an organ transplant.
I am a man and will use contraception during the study if my partner could become pregnant.
Participant Groups
The trial is testing CELZ-201's safety and effectiveness when given through an artery in patients who've recently been diagnosed with Type 1 Diabetes Mellitus. A control group will not receive CELZ-201. The goal is to see if this treatment can help manage diabetes better than current standard care.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: CELZ-201 Treatment GroupExperimental Treatment1 Intervention
Participants in this group will receive a single dose of CELZ-201, in addition to standard of care of care for Type 1 Diabetes treatment.
Group II: Control GroupPlacebo Group1 Intervention
Participants in this group will receive standard of care for Type 1 Diabetes only.
CELZ-201 Administration is already approved in United States for the following indications:
🇺🇸 Approved in United States as CELZ-201 for:
- Type 1 Diabetes Mellitus (expanded access therapy)
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Diabetes Research Institute, University of Miami Miller School of MedicineMiami, FL
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Who is running the clinical trial?
Creative Medical Technology Holdings IncLead Sponsor
References
Clinical update on the use of immuno modulators (antiCD3, GAD, Diapep277, anti-IL1) in type 1 diabetes. [2019]In type 1 diabetes, beta cells are attacked and destroyed by auto reactive T cells causing major impairment of blood glucose metabolism and, ultimately, the development of life-threatening complications. Currently, the treatment of this chronic disease is based on the use of endogenous insulin and no curative therapies are available. Treatment approaches in this respect need to be directed toward the primary causes of the disease tackling beta cells' auto reactive T cells. The goal of any curative intervention in type 1 diabetes is the preservation of insulin-secreting cells. This may be achieved by the abrogation of the pathogenic reactivity to beta cell auto antigens while preserving full capacity to generate a normal immune response against foreign antigens. In this review, some of the most promising drugs for immune intervention in type 1 diabetes are presented and discussed including phase 3 clinical trials that involve: DiaPep277, Anti-CD3 Otelixizumab, Glutamic Acid Decarboxylase (GAD) and anti-IL1 receptor antagonist. These approaches are currently being tested in international multicenter trials and all of them have a very similar outcome in terms of a beneficial effect on beta cells.
Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial. [2022]Protégé was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized ≤6 weeks after diagnosis, HbA1c
Prevention strategies for type 1 diabetes mellitus: current status and future directions. [2018]Type 1 diabetes mellitus affects about 1 in 300 people in North America and Europe. Epidemiological studies indicate that the incidence and thus prevalence of type 1 diabetes is rising worldwide. Intervention in autoimmune type 1a diabetes could occur at the time of diagnosis or, preferably, prior to clinical presentation during the 'prediabetic' period (e.g. prevention). Prediabetes is best recognised by the detection of islet autoantibodies in the serum. Promising intervention strategies include monoclonal antibody therapies (e.g. anti-CD3, anti-CD25, anti-CD52 or anti-CD20 monoclonal antibodies), immunosuppression (e.g. calcineurin inhibitors, B7 blockade, glucocorticoids, sirolimus (rapamycin), azathioprine or mycophenolate mofetil), immunomodulatory therapies (e.g. plasmapheresis, intravenous immunoglobulin, cytokine administration, adoptive cellular gene therapy) and tolerisation interventions (e.g. autoantigen administration or avoidance, altered peptide ligand or peptide-based therapies). To date, islet and pancreas transplantation have essentially been reserved for patients with long-standing diabetes who have complications and are also in need of a concurrent kidney transplant. None of the therapies attempted to date has produced long-term remissions in new-onset type 1 diabetes patients and no therapies have been shown to prevent the disease. Nevertheless, with advances in our understanding of basic immunology and the cellular and molecular mechanisms of tolerance induction and maintenance, successful intervention therapies will be developed. The balance between safety and efficacy is critical. Higher rates of adverse events might be more tolerable in new-onset type 1 diabetes patients if the therapy is extremely effective at inducing a permanent remission. However, therapies must not harm the beta-cells themselves or any organ system that is a potential target of diabetes complications, such as the nervous system, retina, cardiovascular system or kidney. In the treatment of prediabetes, successful therapies should provide a level of safety similar to that of currently used vaccines and a high level of efficacy.
A century later, still fighting back: antigen-specific immunotherapies for type 1 diabetes. [2021]Type 1 diabetes (T1D) is a chronic metabolic disease caused by the autoimmune destruction of insulin-producing β-cells. Ever since the 1920s, the fate of patients suffering from T1D was dramatically improved owing to the isolation and production of insulin, and the scientific field has largely progressed as a result of the evidence gathered about its underpinnings and mechanisms. The last years have seen this knowledge transformed into actual antigen-specific immunotherapies with potential to restore selectively the breach of tolerance to β-cell autoantigens and halt the autoimmune aggression. However, so far, the results of both prevention and reversion trials in T1D have been rather discouraging, so there is still an urgent need to optimize those immunotherapies and their associated factors, for example, posology and administration patterns, route and timing. In this review, we look back on what has been achieved in the last century and identify the main autoantigens driving the autoimmune attack in T1D. Then, we take a deep dive into the numerous antigen-specific immunotherapies trialed and the ones still at a preclinical phase, ranging from peptides, proteins and agent combinations to gene transfer, nanoparticles, cell-based strategies and novel approaches exploiting naturally occurring tolerogenic processes. Finally, we provide insight into the several features to be considered in a T1D clinical trial, the ideal time point for intervention and the biomarkers needed for monitoring the successful regulatory effect of the antigen-specific immunotherapy. Although further research and optimization remain imperative, the development of a therapeutic armamentarium against T1D autoimmunity is certainly advancing with a confident step.
Efficacy and safety of low-dose otelixizumab anti-CD3 monoclonal antibody in preserving C-peptide secretion in adolescent type 1 diabetes: DEFEND-2, a randomized, placebo-controlled, double-blind, multi-centre study. [2018]Phase III DEFEND-2 investigated whether otelixizumab (3.1 mg over 8 days) preserved C-peptide secretion in patients with new-onset Type 1 diabetes, focusing on adolescents (12-17 years).
Improving the detection and management of type 1 diabetes. [2016]Type 1 diabetes affects around 370,000 adults in the UK, about 10% of all those diagnosed with diabetes. In type 1 diabetes there is a lack of beta cell insulin secretion as a result of autoimmune destruction of the beta cells. However, patients are not affected by insulin resistance, and so do not routinely experience the features of metabolic syndrome that occur in type 2 diabetes. NICE recommends considering further investigation with autoantibody testing or measurement of C-peptide when: type 1 diabetes is suspected but the presentation includes atypical features (e.g. age ≥50, BMI ≥ 25 kg/m2, slow evolution of hyperglycaemia or long prodrome); type 1 diabetes has been diagnosed and treatment started but there is a clinical suspicion that the patient may have a monogenic form of diabetes, and C-peptide and/or autoantibody testing may guide the use of genetic testing; classification is uncertain, and confirming type 1 diabetes would have implications for therapy. Structured education is the cornerstone of care providing tools to allow effective self-management. Following a new diagnosis of type 1 diabetes structured education should be offered within 12 months. Newly diagnosed patients should be offered a regimen including a basal (long-acting) insulin with bolus (rapid-acting) insulin given at mealtimes. The optimal regimen, which should be offered from diagnosis, is a combination of twice daily insulin detemir and a rapid-acting analogue given at mealtimes. However, where glycaemic control is already optimised on an alternative insulin regimen this should not be discontinued.
Soluble Antigen Arrays Efficiently Deliver Peptides and Arrest Spontaneous Autoimmune Diabetes. [2023]Antigen-specific immunotherapy (ASIT) offers a targeted treatment of autoimmune diseases that selectively inhibits autoreactive lymphocytes, but there remains an unmet need for approaches that address the limited clinical efficacy of ASIT. Soluble antigen arrays (SAgAs) deliver antigenic peptides or proteins in multivalent form, attached to a hyaluronic acid backbone using either hydrolysable linkers (hSAgAs) or stable click chemistry linkers (cSAgAs). They were evaluated for the ability to block spontaneous development of disease in a nonobese diabetic mouse model of type 1 diabetes (T1D). Two peptides, a hybrid insulin peptide and a mimotope, efficiently prevented the onset of T1D when delivered in combination as SAgAs, but not individually. Relative to free peptides administered at equimolar dose, SAgAs (particularly cSAgAs) enabled a more effective engagement of antigen-specific T cells with greater persistence and induction of tolerance markers, such as CD73, interleukin-10, programmed death-1, and KLRG-1. Anaphylaxis caused by free peptides was attenuated using hSAgA and obviated using cSAgA platforms. Despite similarities, the two peptides elicited largely nonoverlapping and possibly complementary responses among endogenous T cells in treated mice. Thus, SAgAs offer a novel and promising ASIT platform superior to free peptides in inducing tolerance while mitigating risks of anaphylaxis for the treatment of T1D.
Peptide immunotherapies in Type 1 diabetes: lessons from animal models. [2019]Insulin dependent diabetes mellitus (Type 1 diabetes, T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells by proinflammatory autoreactive T cells. In the past, several therapeutic approaches have been exploited by immunologists aiming to regulate the autoimmune response; this can occur by deleting lymphocyte subsets and/or re-establishing immune tolerance via activation of regulatory T cells. The use of broad immunosuppressive drugs was the first approach to be explored. Subsequently, antibody-based immunotherapies failed to discriminate between autoreactive versus non-autoimmune effectors. Antigen-based immunotherapy is a third approach developed to manipulate beta cell autoimmunity. This approach allows the selective targeting of disease-relevant T cells, while leaving the remainder of the immune system intact. Animal models have been successfully employed to prevent or treat T1D by injection of either the self proteins or peptides derived from them. Peptide immunotherapies have been mainly experimented in the NOD mouse spontaneous model of disease. In this review we therefore report the main approaches that rely on the use of peptides obtained from relevant autoantigens such as glutamic acid decarboxylase, isoform 65 (GAD65), insulin, proinsulin and islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP). Protective peptides have proven to be effective in treating or delaying the diabetic process. We also highlight the main difficulties encountered in extrapolating data to guide clinical translational investigations in humans.
Insulin as a primary autoantigen for type 1A diabetes. [2022]Type 1A diabetes mellitus is caused by specific and progressive autoimmune destruction of the beta cells in the islets of Langerhans whereas the other cell types in the islet (alpha, delta, and PP) are spared. The autoantigens of Type 1A diabetes may be divided into subgroups based on their tissue distributions: Beta-cell-specific antigens like insulin, insulin derivatives, and IGRP (Islet-specific Glucose-6-phosphatase catalytic subunit Related Peptide); neurendocrine antigens such as carboxypeptidase H, insulinoma-associated antigen (IA-2), glutamic acid decarboxylase (GAD65), and carboxypeptidase E; and those expressed ubiquitously like heat shock protein 60 (a putative autoantigen for type 1 diabetes). This review will focus specifically on insulin as a primary autoantigen, an essential target for disease, in type 1A diabetes mellitus. In particular, immunization with insulin peptide B:9-23 can be used to induce insulin autoantibodies and diabetes in animal models or used to prevent diabetes. Genetic manipulation of the insulin 1 and 2 genes reciprocally alters development of diabetes in the NOD mouse, and insulin gene polymorphisms are important determinants of childhood diabetes. We are pursuing the hypothesis that insulin is a primary autoantigen for type 1 diabetes, and thus the pathogenesis of the disease relates to specific recognition of one or more peptides.
Construction of a novel vaccine by conjugating a B-cell epitope of DPP4 to peptide IA2(5)-P2-1 to significantly control type 1 diabetes in NOD mice. [2018]Type 1 diabetes is a chronic organ-specific autoimmune disease in which selective destruction of insulin-producing β cells leads to impaired glucose metabolism and its attendant complications. IA2(5)P2-1, a potent immunogenic carrier which designed by our laboratory, can induce high titer specific antibodies when carry a B cell epitope, such as B cell epitopes of DPP4, xanthine oxidase, and Urate transporter protein. In this report, we describe a novel multi-epitope vaccine composing a peptide of DPP4, an anti-diabetic B epitope of Insulinoma antigen-2(IA-2) and a Th2 epitope (P2:IPALDSLTPANED) of P277 peptide in human heat shock protein 60 (HSP60). Immunization with the multi-epitope vaccine in non-obese diabetic (NOD) mice successfully induced specific anti-DPP4 antibody, inhibited plasma DPP4 activity, and increased serum GLP-1 level. Moreover, this antibody titer was correlated with the dose of immunization (20μg, 100μg). Inoculation of this vaccine in NOD mice significantly control blood glucose level, improved glucose excursion and increased insulin level in vivo. Consistent with a lower diabetic and insulitis incidence, a induced splenic T cells proliferation and tolerance were observed. IFN-γ secretion reduced and IL-10 increased significantly in the D41-IA2(5)-P2-1 treated mice compared to P277 and control group due to the potential immunomodulatory effect of the epitope in the vaccine. Immunohistochemical analysis and cytometry showed a rebalance of Th1/Th2 in NOD mice. Our results demonstrate that this multi-epitope vaccine may serve as a promising therapeutic approach for type 1 diabetes.