Objective
Primary objective: The T1D-P-VTep builds on the going JDRF funded Ver-A-T1D trial comparing verapamil with placebo. The primary objective of the current trial (T1D-P-VTep) is to determine the changes in stimulated C-peptide response during the first two hours of a mixed meal tolerance test (MMTT) after 12 months adjusted for baseline for 360mg Verapamil SR administered orally once daily versus the combination of 360mg Verapamil SR administered orally once daily plus teplizumab 9.0mg/m2 given over 12 days and repeated 6 months later. This will demonstrate the ability of this combination to preserve beta cell function better than verapamil alone.
Secondary objectives:
1. To provide evidence on safety of the combination of verapamil with teplizumab.
2. To establish a wider platform (T1D-Plus) trial design for rapid testing of combination beta cell preserving therapies in new-onset T1D
3. To demonstrate the value of adaptive trial design elements incorporated into the study:
a. Sharing of control subjects with other studies for efficiency by use of shared recruitment and assessment criteria
b. Early “fail fast” assessment to terminate the trial early if there is little prospect of benefit.
Background Rationale
Despite recent advances in technology, it remains very challenging to control blood glucose levels to idealy levels with insulin in type 1 diabetes (T1D). The pancreatic beta cells that normally make insulin sense the start of a meal and the arrival of food in the gut as well as the earliest rises in glucose as it is absorbed and deliver their insulin not under the skin but via the portal vein directly to the liver, a key site in the body for glucose storage and release. Even with current technology , it remains difficult to mimic this highly sophisticated biological system. Less than 30% of all children and adults, with T1D, achieve the levels of glucose control needed to prevent long-term complications altogether. Even for those who do achieve this, reaching these goals still requires a major daily effort on monitoring food and exercise activity and adjusting insulin doses, as well as daily fears about the risk of hypoglyemia or a failure of the insulin delivery system resulting in ketoacidosis and hospital admission. So there is still an urgent need for alternative approaches to treatment of T1D.
By the time type 1 diabetes is diagnosed, the immune system is estimated to have destroyed around 80% of the beta cells. This is the result of the autoimmune process that causes T1D. Fortunately, we do not need 100% of our beta cells to effectively control our blood glucose levels. Preserving 30-40% of our beta cells is probably enough to not need insulin treatment at all, and keeping even 5% of beta cell function makes glucose control with injected insulin much smoother and easier to avoid hypoglycemia, as in the “honeymoon period” that occurs in the first months after diagnosis. Preservation of beta cells can be achieved by treatments that slow or halt the autoimmune process, reducing the damage to the beta cells. Seven different treatments have already been shown in clinical trials to slow the autoimmune process. These “immune” or “beta cell preserving” therapies are given at doses that deliver their benefits with few side-effects. However, none of these therapies individually appears sufficient to halt the autoimmune process altogether. It therefore makes sense to begin to combine these treatments to preserve more beta cells and for longer. It seems logical to choose combinations of treatments that work on the immune system or protect beta cells in different ways, so that the benefits add together without the risk of over-suppressing the immune system.
However, using standard methods, clinical trials of combinations of treatments are more complex and require more trial subjects, time and resource than studies of a single treatment alone. In cancer and other diseases, researchers have got round this problem by developing a new approach to clinical trials, referred to as “adaptive platform trials” in which many treatments or treatment combinations are tested at the same time rather than one after another. This has several advantages. Firstly, only one control group is required to match to all the different treatments. Secondly, the “adaptive design” involves checking the results of each treatment at intervals during the trial to see if there is any suggestion that they are working. If there is no hint of benefit, as judged by a statistical threshold set in advance of starting the study, then recruitment to that treatment is stopped and future people entering the trial are directed towards treatments that are showing promise. This is mathematically quite complex, but methods have been developed that work. Here we request support for one arm of first adaptive platform trial of combinations of beta cell preserving therapies in T1D.
Description of Project
One hundred years after its discovery, insulin remains the only available treatment for type 1 diabetes (T1D). Unfortunately, it is very challenging to match the performance of the body’s own insulin producing beta cells with insulin injected under the skin. An alternative approach is slow or halt the autoimmune process that destroys the insulin making beta cells of the pancreas. Several such treatments (immune therapies) have been developed, but each one individually is not enough to stop the destructive process altogether.
Here we propose the first “adaptive platform trial” of immune therapy combinations in T1D – “T1D Plus”. Funding is requested for one arm of this platform – the comparison of verapamil+teplizumab versus teplizumab alone – T1D-P-VTep. The innovative design in “adaptive platform trials” has been shown to save time and resources in testing combinations of treatments in other conditions such as cancer. Verapamil is a once a day blood pressure tablet that has been licensed in adults for over 50 years but has recently been shown to protect beta cells against damage from inflammation. Teplizumab is an anti-T cell immunotherapy given as an infusion daily for 12 days with the course repeated once more after 6 months. Teplizumab has been shown to slow the autoimmune process and preserve beta cells in 7 different clinical trials and is currently under review by the FDA as the first treatment to delay the onset of T1D.
71 adults (age 18-44) with new-onset T1D diagnosed in the last 6 weeks will be entered into the study and treatment with either verapamil alone or verapamil + teplizumab. As the two drugs operate by very different mechanisms, it is expected that teplizumab can increase the benefit of verapamil on preserving beta cells without increasing the side effect risk. Beta cell function will be monitored at 3 monthly intervals using the standard mixed meal tolerance test and measuring levels of C-Peptide released over a 2 hour period after the meal. As part of the novel “adaptive design”, verapamil alone is currently being retested on the same trial “platform” and if (unexpectedly) it is showing no hint of benefit, the T1D-P-VTep study proposed here will not commence. A similar “interim futility assessment” of T1D-PVTep itself will be conducted 12 months into the study, and if there is no hint of benefit, this trial arm will be terminated early – a so-called “fail-fast” element of the novel design. New participants can then be offered alternative treatment combinations in other arms of the T1D-Plus “platform”, saving on participant time and overall resources. Participants already in the study will be followed up and their data included in the final analysis.
The results of this study will not only indicate whether the combination of verapamil+ teplizumab is better than verapamil alone at preserving beta cells and worth of further study, but also contribute to setting up a platform that can rapidly screen multiple combinations of therapies and substantially accelerate progress towards new treatments that can preserve beta cells. These treatment combinations can then be further testing either in new onset T1D or trialled in studies to prevent the onset of T1D.
Anticipated Outcome
There are multiple anticipated outcomes:
(1) This trial will provide a well powered assessment of whether the addition of teplizumab to verapamil increased the potential to preserve beta cells in new-onset T1D. Clinical outcomes measured will include CGM parameters, hypoglycemia, insulin dose, HbA1c and four different well validated patient reported outcome measures (PROMs) providing a detailed assessment of clinical benefits. The PROMs will include questionnaires to assess diabetes related quality of life, diabetes distress, treatment satisfaction and fear of hypoglycaemia.
(2) At the same time, the study will indicate whether there is any suggestion of additional side-effects or risks associated with combination therapy as compared to verapamil alone.
(3) In parallel with this study, on the same platform separately funded by JDRF, a comparison of verapamil versus placebo is being conducted (Ver-A-T1D). As the entry requirements for the study being propsed in this application, T1D-P-VTep have been designed to be the same as Ver-A-T1D, the results can be combined to make an assessment across the two trials of the comparison of the combination of verapamil+teplizumab verus placebo.
(4) Taken together, the study proposed here will contribute to creating the first adaptive trial platform in new onset T1D that can compare further combination therapies rapidly and efficiently resulting in savings in time and funding.
Note that the combination therapies in the T1D-Plus platform are currently being tested in adults only. This is because Verapamil is currently only licensed and has only been tested for T1D in adults and we are building the T1D-Plus platform on the current Ver-A-T1D trial which is recruiting adults only for the same reasons. However, if successful the design will be extended in future to younger participants.
Relevance to T1D
Combinations of treatments that further improve our ability to slow the autoimmune process that destroys beta cells in T1D have the potential to improve blood glucose control, reduce the variation in blood glucose levels and reduce the frequency and risk of hypoglycemia for people with T1D. This will reduce the risk of long-term complications while at the same time reducing the effort and stress associated with the daily challenge for patients and their families of living with T1D.
In addition, the combination trial platform being tested here will be able in future to test more combinations, including triple therapies to continue to improve on the benefits for patients.
At the same time, therapies that protect and prolong the life of beta cells in recently diagnosed T1D (“stage 3 of the new ADA classification) are also likely to work in people earlier in the disease who still have enough beta cells to able to control their blood glucose levels without need insulin at all (“stage1/2” T1D). As a result, the information gained from this study and the trial platform we are developing will also accelerate progress towards preventing T1D and delaying or preventing the need for insulin.
Finally, the study will establish a platform for rapid assessment of other therapy combinations in new-onset T1D with further benefits for patients.