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July 9th, 2012
Questions e-mailed to me here at The Sheet most often concern clinical trials of the Islet Sheet: typically, “When will they start?” and “How can I be part of the trial?”
To answer the first: they will start when we have proven that the Islet Sheet works in large-animal models of autoimmune diabetes. I am happy to say that, after months of delays, we have started these studies. More on that later.
So how will we select participants in the clinical trials? The first trial will be a collaboration between Islet Sheet Medical and an islet transplantation center, either in the United States or overseas. The physicians at that center are primarily responsible for patient safety, and they view patient selection as an important key to patient safety.
Protocols for clinical trials specify in detail who can be in the trial as well as who must not be; these are called inclusion and exclusion criteria. As an example, let’s look at the most recent large trial in islet transplantation with immune suppression drugs. The criteria for the recently concluded CIT-7 islet transplantation trial are listed below.
Patients who meet all of the following criteria are eligible for participation in the study:
1. Male and female patients 18 to 65 years of age.
2. Ability to provide written informed consent.
3. Mentally stable and able to comply with the procedures of the study protocol.
4. Clinical history compatible with T1D with onset of disease at < 40 years of age, insulin-dependence for ≥ 5 years at the time of enrollment, and a sum of patient age and insulin dependent diabetes duration of ≥ 28.
5. Absent stimulated c-peptide (<0.3ng/mL) in response to a mixed meal tolerance test (MMTT: Boost® 6 mL/kg body weight to a maximum of 360 mL; another product with equivalent caloric and nutrient content may be substituted for Boost) measured at 60 and 90 min. after the start of consumption.
6. Involvement in intensive diabetes management defined as self-monitoring of glucose values no less than a mean of three times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy. Such management must be under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least 3 clinical evaluations during the 12 months prior to study enrollment.
7. At least one episode of severe hypoglycemia in the 12 months prior to study enrollment.
1. Body mass index (BMI) >30 kg/m2 or patient weight ≤50kg.
2. Insulin requirement of >1.0 IU/kg/day or <15 U/day.
3. HbA1c >10%.
4. Untreated proliferative diabetic retinopathy.
5. Blood Pressure: SBP >160 mmHg or DBP >100 mmHg.
6. Measured glomerular filtration rate (using iohexol) of <80mL/min/1.73m2 (or for subjects with an iodine allergy, calculated using the subject’s measured serum creatinine and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation). Strict vegetarians (vegans) with a calculated GFR <70 mL/min/1.73m2 are excluded. The absolute (raw) GFR value will be used for subjects with body surface areas >1.73 m2.
7. Presence or history of macroalbuminuria (>300 mg/g creatinine).
8. Presence or history of panel-reactive anti-HLA antibodies above background by flow cytometry.
9. For female subjects: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 4 months after discontinuation. For male subjects: intent to procreate during the duration of the study or within 4 months after discontinuation or unwillingness to use effective measures of contraception. Oral contraceptives, Norplant®, Depo- Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
10. Presence or history of active infection including hepatitis B, hepatitis C, HIV, or tuberculosis (TB). Subjects with laboratory evidence of active infection are excluded even in the absence of clinical evidence of active infection.
11. Negative screen for Epstein-Barr Virus (EBV) by IgG determination.
12. Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection within one year prior to study enrollment.
13. Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin.
14. Known active alcohol or substance abuse.
15. Baseline Hb below the lower limits of normal at the local laboratory; lymphopenia (<1,000/mL), neutropenia (<1,500/mL), or thrombocytopenia (platelets <100,000/mL). Participants with lymphopenia are allowed if the investigator determines there is no additional risk and obtains clearance from a hematologist.
16. A history of Factor V deficiency .
17. Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) after transplantation (low-dose aspirin treatment is allowed) or patients with an international normalized ratio (INR) >1.5.
18. Severe co-existing cardiac disease, characterized by any one of these conditions:
a) recent myocardial infarction (within past 6 months).
b) evidence of ischemia on functional cardiac exam within the last year.
c) left ventricular ejection fraction <30%.
19. Persistent elevation of liver function tests at the time of study entry. Persistent serum glutamic-oxaloacetic transaminase (SGOT [AST]), serum glutamate pyruvate transaminase (SGPT [ALT]), Alk Phos or total bilirubin, with values >1.5 times normal upper limits will exclude a patient.
20. Symptomatic cholecystolithiasis.
21. Acute or chronic pancreatitis.
22. Symptomatic peptic ulcer disease.
23. Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications.
24. Hyperlipidemia despite medical therapy (fasting low-density lipoprotein [LDL] cholesterol >130 mg/dL, treated or untreated; and/or fasting triglycerides >200 mg/dL).
25. Receiving treatment for a medical condition requiring chronic use of systemic steroids, except for the use of £ 5 mg prednisone daily, or an equivalent dose of hydrocortisone, for physiological replacement only.
26. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
27. Use of any investigational agents within 4 weeks of enrollment.
28. Administration of live attenuated vaccine(s) within 2 months of enrollment.
29. Any medical condition that, in the opinion of the investigator, will interfere with safe participation in the trial.
30. Treatment with any immunosuppressive regimen at the time of enrollment.
31. A previous islet transplant.
32. A previous pancreas transplant, unless the graft failed within the first week due to thrombosis, followed by pancreatectomy, and the transplant occurred more than 6 months prior to enrollment.
Quite a list, isn’t it! Many if not most of the exclusions are for people who should not be on immune suppression drugs. A good example is a pregnant person: these drugs might well do severe damage to a fetus.
The inclusion criteria are designed to limit the trial to autoimmune diabetics who can maximally benefit from the transplant. Most often this means hypoglycemia unawareness. I received one comment from a woman who found this unfair to hard-working diabetics; as she put it, she is ”bitten by control that is too good.” I know that my own control does not meet criterion 8: diabetics in good control are excluded from CIT-7.
Good news, though: it is possible that a clinical trial for the Islet Sheet will have much broader inclusion criteria. CIT-7 includes pharmaceutical immune suppression that severely reduces quality of life. The clinical protocol for the Islet Sheet trial will not include immune suppression. If the Islet Sheet is as safe and effective as we expect, many of the above criteria will be dropped from our clinical study. You and I might be eligible.