Domenic J. Reda, MS, PhD Director Hines Cooperative Studies Program Coordinating Center US Dept of Veterans Affairs

Transcription

1 Domenic J. Reda, MS, PhD Director Hines Cooperative Studies Program Coordinating Center US Dept of Veterans Affairs

2 Mifepristone for Treatment of PTSD Symptoms 2

3 Biology of PTSD People with PTSD have enhanced sensitivity of the HPA axis Elevated corticotropin releasing factor Glucocorticoid-related alterations Stressful conditions result in exaggerated anxiety and hyperarousal responses 3

4 Mifepristone Potent glucocorticoid receptor antagonist Cortisol is a glucocorticoid that is released into the bloodstream during acute stress Glucocorticoid receptor blockade may re-regulate the HPA axis in people with abnormal HPA responses Major psychotic depression PTSD 4

5 Available trials on Mifepristone Safety 600 mg dose wellstudied Primarily in psychotic depression Rash Potential concern about adrenal insufficiency due to suppression No evidence in studies of short-term dosing (up to 7 days) Efficacy Limited evidence of benefit for pyschotic depression Not studied for effect on PTSD symptoms Small study showing potential benefits on HPA re-regulation and symptoms (next slide) 5

6 Lysozyme IC 50-DEX Pilot Trial of Mifepristone for PTSD (Yehuda and Golier) N=17 (8 with PTSD, 9 without) Pre-Treatment Post-Treatment Between Groups Significance Initial Endpoint 4-week Initial to Endpoint Initial to 4-week Mean (SD) Mean (SD) Mean (SD) p-value p-value CAPS score Drug (n=4) (10.24) (19.49) (24.12) Placebo (n=4) (8.77) (31.89) (18.86) a Fig. 2 Effect of mifepristone on GR sensitivity in subjects with and without PTSD Intrusive Symptoms Drug (n=4) (8.06) 8.00 (7.70) 7.50 (9.00) Placebo (n=4) (4.65) (10.30) (9.42) Avoidance Symptoms Drug (n=4) (7.14) (11.44) (10.74) Placebo (n=4) (1.29) (7.05) (5.72) b Hyperarousal Symptoms Drug (n=4) (0.50) (5.56) (9.68) Placebo (n=4) (6.40) (10.53) (5.97) PTSD+ PTSD- BDI Drug (n=4) (5.85) (4.72) (9.15) Placebo (n=4) (12.12) (10.05) (9.54) PCL Drug (n=4) 60 (10.83) (11.79) (15.59) Placebo (n=4) (11.41) (24.17) (16.68) Cortisol (µg/dl) Drug (n=4) (3.52) (5.49) (4.27) Placebo (n=4) (6.16) (4.87) (2.91) c no DRUG mifepristone spironolactone ACTH (pg/ml) Drug (n=4) (29.69) (40.25) (8.08) Placebo (n=4) (14.83) (16.18) (19.33) d Lysosyme IC50 (nm) Drug (n=2) 8.00 (2.55) 5.57 (.76) 6.73 (3.66) Placebo (n=4) 3.27 (2.89) 3.65 (2.06) 5.03 (1.68) GR/cell Drug (n=3) (539.75) (116.89) (770.02) Placebo (n=4) (553.91) (543.84) (683.80)

7 What is an appropriate design approach for the next trial? Phase I safety for 600 mg dose already established Small pilot (n=17) shows: biologic plausibility (positive HPA axis effects) Positive effect on PTSD symptoms Not enough evidence of effect to justify a definitive phase II trial We proposed a Phase II RCT to obtain additional evidence of efficacy and safety FDA agreed 7

8 Study Design Screen for eligibility Randomize 600 mg mifepristone for 7 days Placebo for 7 days Assess at 1, 4 (primary endpoint) and 12 weeks Assess at 1, 4 (primary endpoint) and 12 weeks 8

9 Primary Outcome Measure CAPS-2 (Clinician Administered PTSD Scale) gold standard Treatment response - A 30% reduction in CAPS-2 score from baseline to 4 weeks (binary outcome) 9

10 Sample Size Approach Simon, Wittes & Ellenberg (1985) Ranking and Selection Method An observed difference in responder rate of 15% or greater will provide evidence that one treatment may be superior to the other Desire 90% probability of correctly identifying the more effective treatment group if at least a 15% difference is observed Assumed a placebo responder rate of 40% (conservative) Expected withdrawal rate of 20% Sample size 45 per group 10

11 Alternative Approach Considered Traditional hypothesis testing framework One-sided alpha of.05 and power of 80% Same assumptions about clinically relevant different (15% and placebo responder rate (40%) Sample size 170 per group 11

12 Additional Behind the Scenes Info Study originally designed and started as a 3-arm RCT that included 1200 mg dose (along with palcebo and 600 mg) First patient randomized went to ER for symptoms of lightheadedness and weakness Unblinding was requested Patient was on 1200 mg dose Additional review of prior safety data resulted in dropping the 3 rd arm 12

13 A Pilot Trial to Assess Low-Intensity Ultrasound for Osteoarthritis of the Knee 13

14 Osteoarthritis of the Knee OA is a highly prevalent condition that is associated with aging Two primary characteristics Damage/destruction of knee cartilage Pain Available treatments target the symptoms (pain) but no treatments have been shown to repair cartilage Many people elect total knee replacement when pain is significant and no longer alleviated by other treatments 14

15 Low-Intensity Ultrasound Exogen 4000 is a bone-stimulator that is approved for treatment of some types of bone fractures 15

16 Ultrasound and Cartilage Animal Studies Several animal models have been examined Low-intensity ultrasound increased production of key components of cartilage Chondrocytes Proteoglycans Type II collagen In induced cartilage damage, low-intensity ultrasound slowed further degeneration and accelerated cartilage repair Illustrative results for treatment of animals initiated at 2 months of age, with treatment duration of 4 months. Left: PLIUS-treated. The medial tibial plateau (MTP) shows an intact surface with mild loss of matrix staining. The medial femoral condyle (MFC) shows an intact surface with uniform matrix staining. Right: Untreated control animal. The MTP shows extensive surface fibrillation and deeper fissuring, with greater loss of staining. Staining is with thionin. 16

17 Thoughts on a Study in Humans Device is approved for use in humans with bone fracture Considered a low-risk device Animal studies in OA show positive effects on cartilage No animal data available for OA symptoms (pain, stiffness, function) No studies in humans for treatment of OA We proposed a Phase IIa study to examine effects on cartilage and symptoms 17

18 Study Design Ultrasound For 48 weeks 20 min,/day Randomize Placebo Ultrasound 48 weeks 20 min./day Screen for eligibility Placebo Run-in 4 weeks Placebo response for symptomatic conditions can be a problem Follow-up visits at weeks 2, 4, 8, 12, 24, 36 and 48 Phone calls at weeks 1, 6, 10, 18, 30 and 42 18

19 Primary Outcome Measures Cartilage thickness of the central medial femoral condyle as measured by MRI OMERACT-OARSI Response An improvement in either pain or function of at least 50 percent accompanied by an absolute decrease of at least 20 mm on the visual-analogue scale for pain or function, OR The occurrence of at least two of the following: a) a decrease in pain of at least 20 percent accompanied by a decrease of at least 10 mm on the visual-analogue scale; b) an improvement in function of at least 20 percent and a decrease of at least 10 mm on the visualanalogue scale; c) an increase in the patient s global assessment score by at least 20 percent accompanied by a decrease of at least 10 mm on the visual-analogue scale 19

20 Sample Size Approach Ranking and Selection Procedures for Binomial Data (Simon, Wittes & Ellenberg (1985) and Continuous Data (Gibbons et al) Although cartilage damage plus symptoms defines OA, the two components are not well-correlated The co-primary outcome measures were considered independent measures No adjustment for multiplicity 20

21 Sample Size for Cartilage Thickness Longitudinal MRI data from the Osteoarthritis Initiative (an Epi study) were used to estimate cartilage thickness changes for Placebo Ultrasound A 22% reduction in change (relative to the standard deviation) was the margin to demonstrate potential efficacy 20% withdrawal rate If the 22% reduction is observed, a sample size of 90 per group is needed to provide 90% probability of correctly identifying the potentially superior treatment 21

22 Sample Size for OMERACT-OARSI Response Sample size was based on MRI outcome measure Response rate estimates were obtained from a completed large RCT on treatment of knee OA pain A 10% improvement in the responder rate would be evidence of superiority The placebo responder rate was estimated to be 50% The sample size of 180 provided 88.5% likelihood of correctly identifying the superior treatment 22

23 If this is a low-risk device, why not proceed to a definitive phase III trial? Only potential evidence of efficacy was the cartilage data in animals No data on effect on pain For OMERACT-OARSI response, the sample size for a phase III trial using two-sided alpha of.05 and power of 85% would be 886 For cartilage thickness it would be

24 FDA Responses to IDE Application No concern about safety Phase II trial is acceptable HOWEVER: how will the results of the trial be used to determine whether to proceed to a phase III? Our responses This is not a device company study, no intention for a labelling change Discussed various possibilities depending on whether MRI outcome, OMERACT-OARSI outcome or both are positive 24

25 Randomized Phase II Trial of Botulinum Toxin for BPH 25

26 Botulinum Toxin for Treatment of Benign Prostate Disease Symptoms I was a member of the DSMB Study has been completed and published Background Benign prostate disease is a common condition in older men that can results in difficulties with urination Drug treatments shown to be effective have either targeted relaxation of smooth muscle tissue or shrinking the prostate gland Botulinum toxin might have a beneficial effect on symptoms by action on smooth muscle tissue. Is it safe? 26

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28 Design Non-comparative two-arm randomized phase II trial using Simons Optimal Two-Stage Design Each arm compared with pre-determined threshholds for efficacy and safety Efficacy treatment success defined as a 30% improvement in the AUASI (symptoms) and/or a 30% improvement in QMAX (max urination velocity) from baseline to 3 months Safety no safety issues (SAEs, significant Aes) 28

29 Design (continued) Stage 1 criteria N=24 At least 9 treatment responders No safety issues If these criteria are met, then proceed to stage 2 Stage 2 criteria Additional N=39 (total N=63) At least 25 responders (out of 63) No safety issues Alpha =.05 Power = 90% 29

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31 Results A total of 134 men were randomized and treated (68 with 100 units, 66 with 300 units), with 131 assessed at 3 months and 108 assessed at 12 months. Each dose met the 3-month primary outcome criteria. In the 100 unit arm the mean baseline American Urological Association symptom index of 18.8 decreased by 7.1 and 6.9 at 3 and 12 months, respectively. In the 300 unit arm the baseline of 19.5 decreased by 8.9 and 7.1, respectively. In the 100 unit arm the mean baseline maximum urinary flow rate of 10.0 ml per second increased by 2.5 and 2.2, respectively, and in the 300 unit arm the baseline of 9.6 increased by 2.6 and 2.3, respectively. 31

32 Conclusions The intraprostatic injection of 100 or 300 units of onabotulinum toxin A passed predetermined criteria for treatment efficacy and safety, and a randomized trial with either dose is warranted. The 100 unit dose may be preferable due to similar efficacy with reduced costs and adverse effects. 32