The Insulin Independence Trial (IIT) Evaluating the Safety and Efficacy of Oral Cyclosporine and Oral Lansoprazole for Insulin Independence Among Recent Onset Type 1 Diabetes Patients

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified September 2014 by Perle Bioscience, Inc.
Sponsor:
Information provided by (Responsible Party):
Perle Bioscience, Inc.
ClinicalTrials.gov Identifier:
NCT01762644
First received: January 2, 2013
Last updated: October 3, 2014
Last verified: September 2014
  Purpose

The purpose of this study is to determine if the combination of oral cyclosporine, an immune therapy and oral lansoprazole, a proton pump inhibitor, are effective in rendering insulin independence among recent onset type 1 diabetes patients. This two-arm study is designed to evaluate the safety and efficacy for insulin independence of two FDA-approved therapies among recent onset type 1 diabetes patients.

One of the greatest new insights of today in the field of type 1 diabetes, is the understanding that in man, unlike the success seen in type 1 diabetes mouse models, there is no beta cell regeneration with immune therapy alone. In man, type 1 diabetes is now considered to be a disease of both autoimmunity and lack of beta cell regeneration (Levetan 2103).

More than 500 patients with new onset type 1 diabetes have been given cyclosporine and some studies have demonstrated as high as a 57% insulin-free remission rate that was not sustained due to the lack of beta cell regeneration (Feutren 1986, Bougneres 1988, Eisenbarth 1989, Sobel 2010). Studies among diabetes patients with proton pump inhibitors have shown the potential to increase beta cell mass by 40%, but among type 1 patients without immune protection, such outcomes cannot be not achieved (Singh 2012, Griffin 2014).

The usage of a beta cell regeneration agent such as lansoprazole, in combination with an immune tolerance, like cyclosporine, provides both the potential ability to maintain and regenerate beta cells. This is a new paradigm for the treatment of new onset type 1 diabetes.

More than 60 human trials have been conducted among type 1 diabetes with a variety of different therapies aimed at preventing autoimmune attack on insulin-producing beta cells. None have been as effective as cyclosporine in both slowing the decline in beta cell mass and resulting in the potential for insulin-free remissions. (Canadian-European Randomized Control Trial 1988, Eisenbarth 1989, Skyler 1992, Sobel 2010).

Because cyclosporine is known for its potential side-effects, most notably in the kidney, all previous studies among type 1 patients have carefully monitored kidney function. Follow-up studies for up to 13 years among 285 type 1 patients utilizing cyclosporine for 20 months did not demonstrate renal or other side effects at the dosages that will be used in this trial (Assan 2002).

The most effective initiating dosage for insulin independence in the cyclosporine trials was 7.5 mg/kg/day, but for safety, this study will begin at a lower dosage of 5 mg/kg/day and will monitor kidney function and cyclosporine levels initially on a weekly basis. This study will use only those dosages of cyclosporine that have not demonstrated toxicity to the kidney or resulted in non-reversible side effects among more than 500 patients with recent onset type 1 diabetes treated with cyclosporine.

Lansoprazole has been shown to significantly increase gastrin levels which is associated with increased beta cells. Lansoprazole has also been shown to be safe among patients with new onset type 1 diabetes for one year with a trend toward increased beta cell mass among patients with higher gastrin levels.

In a randomized trial for 12 weeks among 56 patients undergoing pancreatectomy, those randomized to receive lansoprazole had significantly increased gastrin levels, higher insulin levels and improved endocrine function by glucose tolerance testing and less pancreatic atrophy as measured by CT scans (Jang 2003).

The recently completed REPAIR T1D trial among newly diagnosed type 1 patients used lansoprazole and GLP-1 therapies for 1 year for beta regeneration failed to meet its endpoint of increased stimulated C-peptide. Lack of maintenance or regeneration of beta cells was specifically noted to have likely been due to lack of usage of immune therapy to protect beta cells (Griffin 2014, Rigby 2014).

Those patients in REPAIR T1D, who did achieve gastrin and GLP-1 levels above those in the control group had a trend towards improved preservation of C-peptide with a suggestion of a decreased rate of fall of C-peptide through 12 months (Griffin 2014 Appendix Supplemental data). Glucose levels also trended lower than controls in the intervention arm with gastrin levels above the control arm (Griffin 2014 Appendix Supplemental data). In humans, the newly forming beta cells are under the greatest immune attack among type 1 patients (Meier 2006). REPAIR T1D underscores the importance for both immune therapy with a regeneration therapy among type 1 patients (Griffin 2014, Rigby 2014).

The combination of cyclosporine and a proton pump inhibitor has the potential to demonstrate maintenance and expansion of residual beta cells. This combination therapy provides the unique ability for patients to become insulin independent.

For a request of references, please email info@perlebioscience.com


Condition Intervention Phase
Type 1 Diabetes
Drug: Oral Cyclosporine A and Oral Lansoprazole
Drug: Oral Placebos
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A PhaseIIB/III, Randomized, Double-Blind, Multinational, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Diminishing Insulin Requirements Utilizing Oral Cyclosporine With Oral Lansoprazole in Children and Adults With Recent-Onset Type 1 Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by Perle Bioscience, Inc.:

Primary Outcome Measures:
  • Stimulated C-peptide (area under the curve) among recently diagnosed patients treated with oral cyclosporine and oral lansoprazole [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Insulin Independence among recently diagnosed patients treated with oral cyclosporine and oral lansoprazole [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 130
Study Start Date: February 2015
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Oral Cyclosporine and Oral Lansoprazole Drug: Oral Cyclosporine A and Oral Lansoprazole
Oral Cyclosporine A dosed at 5.0 mg/kg/day in two divided doses and adjusted based on trough levels. Lansoprazole dosed at 60 mg daily in two divided doses for patients 8-16 years of age and 120 mg daily in two divided doses for patients aged 17-30. At 24 weeks, all patients who are insulin independent will be given the option to continue on a safety extension study with active drugs for an additional 24 weeks with follow up. Patients who are not insulin independent at 24 weeks will be followed for additional secondary endpoints for a total of 24 more weeks.
Placebo Comparator: Oral Placebos Drug: Oral Placebos
Two oral placebos are provided to patients twice daily. The placebos may be in the form of pills/capsules or oral suspension.

  Eligibility

Ages Eligible for Study:   8 Years to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subjects 8-30 years old.
  2. Subjects under the age of 18, shall have an acceptable surrogate capable of giving consent on the subject's behalf
  3. Body weight > 30 kg
  4. Diagnosis of diabetes mellitus according to the American Diabetes Association (ADA) criteria
  5. Randomization on Study Day 0 within 12 weeks of the first visit to any physician for symptoms or signs of diabetes
  6. Requires insulin for T1DMbetween diagnosis and administration of study drug
  7. Diagnosis of T1DM as evidenced by one positive result on testing for any of the following antibodies at screening: Islet-cell autoantibodies 512 (ICA512)/islet antigen-2 (IA-2), Glutamic Acid Decarboxylase (GAD) autoantibodies, Insulin autoantibodies or Zinc Transporter 8 Antibody (ZnT8)
  8. Stimulated C-peptide greater than 0.6 ng/mL=0.2nmol/L=200 pmol/L=0.2 pmol/mL
  9. Females must have a negative pregnancy test and practice acceptable contraception [e.g., oral, intramuscular, or implanted hormonal contraception, sexual partner with nonreversed vasectomy (with azoospermia in 2 tests), 2 barrier methods (e.g., condom, diaphragm, or spermicide), or intrauterine device] or be post-menopausal (at least 1 year without spontaneous menses) or surgically sterile (tubal ligation or hysterectomy at least 6 months prior to enrollment)]. Females of childbearing potential must undergo pregnancy testing within 24 hours prior to administration of the first dose of study drug.

Exclusion Criteria:

  1. Any medical condition that, in the opinion of the investigator, would interfere with safe completion of the trial
  2. Prior administration of immunosuppressants, including in a clinical trial for type 1 diabetes
  3. Participation in any type of therapeutic drug or vaccine clinical trial within the last 12 weeks before randomization at Study Day 0
  4. Pregnant females or lactating females Current therapy with GLP-1 receptor agonists (e.g., exenatide or pramlintide), or any other agents that might stimulate pancreatic beta cell regeneration or insulin secretion
  5. Current treatment with oral antidiabetic agents
  6. Evidence of active or latent tuberculosis
  7. Vaccination with a live virus or organism within the 8 weeks before randomization continuing through week 52 of the study
  8. Influenza vaccination with a killed virus, including booster vaccinations, within 4 weeks before or after each dosing cycle
  9. Vaccination with other antigens or killed organisms within 8 weeks before or after each dosing cycle
  10. Any infectious mononucleosis-like illness within the 6 months before randomization
  11. Systolic or diastolic blood pressure >140 mmHg and 90 mmHg, respectively, as measured by an appropriately sized cuff
  12. A body mass index (BMI) >28 kg/m2
  13. Worsening retinopathy, angina, or congestive heart failure
  14. A history or presence of acute or chronic pancreatitis
  15. A history or presence of any illness, disease, or condition that could impact patient safety or evaluability of drug effect, in the Investigator's opinion
  16. An episode of severe hypoglycemia (defined as a change in mental status requiring assistance) during the prior 30 days
  17. An episode of diabetic ketoacidosis during the prior 6 months;
  18. Received any new hypoglycemic medications within the past 3 months
  19. An aspartate transaminase (AST), alanine transaminase (ALT), or total bilirubin level >2 times the upper limit of normal (ULN)
  20. A blood urea nitrogen (BUN) level >50 mg/dL or a serum creatinine level >1.3 mg/dL
  21. A serum amylase level >1.5 times the ULN or a serum lipase level >2 times the ULN
  22. A history of substance abuse or dependence in the past year as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM V) criteria.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01762644

Contacts
Contact: Claresa S. Levetan, MD info@perlebioscience.com

Sponsors and Collaborators
Perle Bioscience, Inc.
Investigators
Principal Investigator: Claresa S. Levetan, MD Perle Bioscience, Inc.
  More Information

Additional Information:
Publications:

Responsible Party: Perle Bioscience, Inc.
ClinicalTrials.gov Identifier: NCT01762644     History of Changes
Other Study ID Numbers: PRL001
Study First Received: January 2, 2013
Last Updated: October 3, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Perle Bioscience, Inc.:
Type 1 Diabetes
Insulin Independence
Beta Regeneration
Immune Tolerance Agent
Lanzoprazole
Cyclosporine

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Autoimmune Diseases
Endocrine System Diseases
Glucose Metabolism Disorders
Immune System Diseases
Metabolic Diseases
Cyclosporine
Cyclosporins
Dexlansoprazole
Insulin
Insulin, Globin Zinc
Lansoprazole
Anti-Infective Agents
Anti-Ulcer Agents
Antifungal Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Gastrointestinal Agents
Hypoglycemic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Proton Pump Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014