Clinical Trial Pathways for Renal Denervation in Moderate to Resistant Hypertension Laura Mauri, M.D., M.Sc. Brigham and Women’s Hospital Harvard Medical School Boston, MA

Disclosures - Laura Mauri, M.D., M.Sc.   Research grants from Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly, Daiichi Sankyo, Bristol-Myers Squibb, Biotronik, and Sanofi-Aventis Consulting Medtronic, Eli Lilly, Biotronik, ReCor, St. Jude

Study design in medical device evaluation Each study with a specific objective Designed to address key areas of uncertainty Tested in a population with unmet need Comparison of efficacy and safety to current standards of care Feasible to conduct Reliable to make inference from to clinical practice What is the key objective at each phase? Feasibility – signal of efficacy, Pivotal, reliable assessment of efficacy in the intended population.

Early efficacy and safety Procedural guidance Pivotal Feasibility Proof of concept Early efficacy and safety Procedural guidance Pivotal Efficacy in intended population Post-Market Effectiveness and safety in practice Spectrum of potential studies: focussed to real world: Single arm (out), randomized non blinded, randomized blinded sham control, pragmatic trial Take home: 1. still need randomized blinded, sham control until efficacy is clear; safety question depends on similarity to tested therapy (e.g. HTN 3 results good, but may not be generalizable). Once efficacy is clear, broader trials : e.g. I and E; endpoints, more practical (lack of blinding) are reasonable. objectives: first show efficacy, second show safety, third what is the role in patient care? This is the biggest question that defines the study design, and the most challenging. -is RDN better than medications in patients who remain hypertensive on a maximally dosed multidrug regimen (HTN 3) – critique is that it applies to a narrowly defined population and the control arm is not being treated as they would be under optimal non clinical trial care. -is RDN as good as medications, but easier for patients to comply with (potential of preventing clinical endpoints, cost savings for treatment of HTN and complications) this is a non inferiority design Question of population follows from there – it is as clinically relevant in low and high risk patients: and in both need to see early determination of efficacy before embarking on larger trials. Prior feasibility studies provided insufficient evidence Next set of feasibility studies must meet higher bar for efficacy Line between objectives of feasiblity and pivotal blurred for RDN

Clinical Trials for Renal Denervation Device Evaluation: Objectives Resolve uncertainty Address unmet need Understand technology Feasible conduct Reliable result Does it work? In whom does it work? How does it work? Study Execution Avoiding Bias Target population for a pivotal trial?

Clinical Trials for Renal Denervation Device Evaluation: Lessons Learned Resistant HTN is an extreme form of HTN Improved BP control occurs in the control arm Medication changes are common Clarity on physiologic mechanism was limited Sham control is necessary Target population for a pivotal trial?

Bhatt et al. NEJM 2014. Bhatt et al. NEJM 2014. 63% screen failure rate Goal of 2 week screening was to ensure stable medications on maximal tol doses – this is important to allow stable medications during the analysis period. Was this sufficient? Bhatt et al. NEJM 2014. Bhatt et al. NEJM 2014.

Changes in Antihypertensive Medication   Denervation group (n=364) Sham group (n=171) Baseline number of medications 5.1 ± 1.4 5.2 ± 1.4 6 month number of medications 5.0 ± 1.4 5.2 ± 1.6 Medication change SV1 to SV2 18 (4.9%) 13 (7.6%) Any medication change between baseline and 6 months 139 (38.2%) 72(40.3%) >1 change between baseline and 6 months 119 (32.7%) 60 (35.1%) Decreased number of medications or doses 52(14.3%) 23 (12.8%) Increased number of medications or doses 31 (8.5%) 17 (9.9%) Undetermined 56 (15.3%) 32 (18.7%) Medication change related to an adverse event or symptom change 98 (26.9%) 53 (31.0%) Medication change related to SBP <115 mm Hg 13 (3.6%) 2(1.2%) Medication change related to SBP increase >15 mm Hg 14 (3.8%) 7 (4.1%) Other reasons (physician discretion) 72 (19.8%) 41 (24.0%) The screening period resulted in 5 meds on average, but changed in many, and frequently over 6m. Kandzari D, Bhatt DL, Brar S, et al. Eur Heart J 2014 Nov 16 Data are mean (SD) or n (%); SV = screening visit

Medication Changes During Trial ~40% (n = 211) of trial subjects required medication changes between baseline and primary efficacy endpoint assessment: 69% of first medication changes were medically necessary 121 patients had a med change due to an adverse event 80 patients had a med change due to a drug side-effect ~69% were changes in drugs at maximally-tolerated dose Patients With Medication Changes (%) But medications were not stable during the analysis period of the study Update references N = 139 N = 72 Kandzari D, Bhatt DL, Brar S, et al. Eur Heart J 2014 Nov 16

Non-African American and African American Subgroups It wasn’t just that it didn’t work in AA, it was that the sham group improved so dramatically. Why? Suggests larger hawthorne effect in AA. Not necessarily driven by race, but by medications that were difficult to comply with more frequently prescribed to AA (vasodilators). Suggests that methods to use uniform medication regimens will be important in next trials P=0.012 P=0.641 Baseline SBP, mm Hg 179.5 178.6 180.6 183.9 Kandzari D, Bhatt DL, Brar S, et al. Eur Heart J 2014 Nov 16

Time since screening (days) Trial Recruitment Improves Glycemic Control: Type II DM 3 US Studies, 611 Subjects 0.25% reduction at >28d Effect inversely proportional to baseline HbA1C Change in HbA1C (%) Observed in medical trials of HTN. Not unique to this study, or HTN. Authors conclude that because effects were present in both Type I European trials and Type II (Type I with selection for good control) – not explained by regression to the mean. But altered behavior from education (not specified in protocols) or increased interest and motivation. Time since screening (days) Gale, E. A. Diabetes Care. 2007 Dec;30(12):2989-92.

Renal Denervation: Randomization and Blinding Many device trials are single arm, especially feasibility Why have a blinded sham? Reliable determination of efficacy is necessary for RDN Unblinded studies are appropriate when outcome is predictable in the study population, and there is minimal potential effect of placebo For renal denervation, impact of placebo effect or changes in medication compliance could both confound assessment of efficacy if blinding absent

Not every medical device trial needs randomization and blinding Not every medical device trial needs randomization and blinding. Single arm trials for coronary stents, for heart valves, why not RDN? Slide showing positive unblinded trial positive results RDN, others. HTN 2, HTN 3.

Key Study Design Choices Inclusion Criteria Choose for proof of concept but also to anticipate intended population Screening Ensure homogeneity of baseline BP on stable medical regimen Randomization and Blinding/Sham Control regimen and follow up Protocol specified, fixed or recommended medications, with clear directive for changes Reduce drop outs but preserve safety Assessment of futility Not planning to show specific designs, because there is enough uncertainty in target population But these choices may apply to both feasilbity and pivotal trials

Controversial Design Choices Target population(s) Optimal follow-up duration Assess maximal effect Assess durability of effect, or late effects Cross over Incentive for enrollment limits ability to detect late effects Assessing medication compliance Assessing mechanism of action of RDN

Study population Proof of Concept or Intended population Denovo HTN Medication replacement Moderate HTN Resistant HTN False dichotomy of proof of concept vs intended population Results in one population may not predict results in another, e.g. vast difference in de novo and severe resistant.

Clinical Trial Design for Renal Denervation Conclusions (1) Randomization and blinding remain important Target population and role of therapy are the most challenging questions RDN to improve control over max tolerated medication regimen in severe resistant hypetension may be unrealistic even for an effective therapy

Clinical Trial Design for Renal Denervation Conclusions (2) Next feasibility data are needed to consider effect in varied populations – potential benefit in early and late hypertension Once efficacy is established, effectiveness can be tested more broadly (e.g. non-inferiority of replacement of medications, but easier for patients to comply with than medication, and therefore, potentially superior) First, it may be reasonable to reconsider the target population for RDN. While patients with resistant hypertension represent an important unmet clinical need, the reduction in BP associated with trial participation, even in the sham-procedure arm, suggested that some of these patients were not truly treatment-resistant. In addition, whether RDN is best suited to the physiology of individuals on heterogeneous pharmacologic regiments of 4 drugs or more, versus those with more moderate hypertension, remains unknown, but could be of interest if procedural risks are determined to be low. Study participants with higher starting BPs have had a greater likelihood for improvement mathematically in single arm studies; however, in a controlled clinical trial, it is not known whether more moderate levels of pressure, with fewer antihypertensive agents, might be more responsive to RDN. Finally here, BP has been an acceptable surrogate endpoint to determine the effectiveness of new pharmacologic therapies for over 4 decades. In therapies also documented to be safe, it is reasonable to expect that the same mechanism of benefit would apply to RDN. While the SYMPLICITY HTN-3 study required a superiority margin (not just a statistically significant improvement) to conclude superiority, if the risk of a candidate RDN therapy is documented to be minimal such a margin perhaps should not be a requirement. In prior studies, crossing over of study participants initially randomized to the sham procedure has been included to encourage participation, but this occurrence also prevents detection of later treatment effects. The one determinant of trial design that must be emphasized here is the value of a sham control if BP is the primary endpoint, lest the value of RDN be overestimated without a proper control. Past device research has clearly demonstrated the importance of a control group in a well-designed cardiovascular technology trial of angina pectoris [33]. However, it is likely that the sham effect that was measured in SYMPLICITY HTN-3 is not just a placebo effect, but also the effect of differing medication adherence in a trial setting. Therefore, in considering the potential value of RDN, it may be important in future studies to consider that better “compliance” with therapy, e.g. the potentially more durable effect of RDN, may be an important value to RDN versus medical therapy in a real world setting. Finally, if RDN technologies mature in the future, noninferiority designs comparing RDN with medical therapy might be reasonable to consider as patients and physicians may place value on replacement therapy. A major challenge to this approach would be demonstrating a financial value to this strategy given the number of low cost medications that currently exist to treat hypertension.