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![Composite Safety Endpoint - KM1
Log-Rank p-value = 0.962
Standard PTA
DCB
Months
Survival DCB PTA
Days %[95% CI] %[95% CI]
30 days 99.4% [97.5, 99.8] 99.4% [95.6, 99.9]
183 days 94.0% [90.7, 96.2] 94.1% [88.9, 96.9]
FreedomfromPrimarySafetyEvent
1Not pre-specified for hypothesis testing and not adjusted for multiplicity](https://image.slidesharecdn.com/1110-1120-dcb-btk-pairs-160212120203/75/DRUG-ELUTING-BALLOONS-38-2048.jpg)
![Primary Patency - KM1
Months
%FreefromPrimaryPatencyEvent
Survival DCB PTA
Days %[95% CI] %[95% CI]
30 days 99.7% [97.8, 100.0] 100.0% [N/A]
183 days 92.3% [88.6, 94.8] 82.7% [75.6, 87.8]
Standard PTA
DCBLog-Rank p-value = 0.003
1Not pre-specified for hypothesis testing and not adjusted for multiplicity](https://image.slidesharecdn.com/1110-1120-dcb-btk-pairs-160212120203/75/DRUG-ELUTING-BALLOONS-39-2048.jpg)
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- 1. DCB: What IsThe Evidence? Carlos I. Mena, M.D., FACC, FSCAI Assistant Professor of Medicine Medical Director Vascular Medicine Yale School of Medicine, Yale New Haven Hospital New Haven, CT
- 2. Endoarterial Continuum ofCare MEDICAL THERAPY PTA STENTS BYPASS AMPUTATION HEALTHY LEG ATHERECTOMY Less Invasive Decreasing Options/Irreversibility More Invasive Where do NEW procedures & devices fit? SC1196092013A 2 |
- 3. What is thePathway to Follow
- 4. An Effective DCBCatheter Formulation Should… – Use the lowest possible dose needed to achieve therapeutic tissue levels – Retain drug on the balloon during transit to the lesion – Ensure rapid drug transfer upon balloon inflation – Produce a uniform, durable, transfer efficient coating – Demonstrate histologic “Drug-Effect” at least 28 days post treatment by light microscopy in preclinical models as the experience from DES is extensive
- 5. Covidien’s ILLUMENATE ClinicalTrial Series Study Design ILLUMENATE FIH First in human, NR, MC study; 2 cohorts (pre-dil w/uncoated PTA balloon followed by DCB or Direct DCB) ILLUMENATE EU Prospective, R, MC trial safety & effectiveness trial; Stellarex™ DCB vs. uncoated standard PTA balloon ILLUMENATE Pivotal Prospective, R, MC trial safety & effectiveness trial; Stellarex™ DCB vs. uncoated standard PTA balloon ILLUMENATE Global Prospective, NR, MC single-arm trial; further evaluate the safety & effectiveness of Stellarex™ DCB ILLUMENATE PK Prospective, NR, SC trial; describe pharmacokinetics of PTX in blood when lesions treated with Stellarex™ DCB SC1196092013A 5 |
- 6. Bard Peripheral ClinicalTrial Program Indication Study Design # Pts # Sites Arms Primary EP PI(s) SFA LEVANT I (FIH) RCT 101 EU Multicenter DCB vs. PTA LLL@6M D. Scheinert LEVANT 2 RCT 476 IDE Global Multicenter DCB vs. PTA Safety & Efficacy D. Scheinert K. Rosenfield LEVANT 2 Continued Access Registry 650 IDE Global Multicenter DCB Alone Rare Adverse Events D. Scheinert K. Rosenfield LEVANT Global SFA Registry Registry ~1000 EU Multicenter DCB Alone Event free survival NA BTK Lutonix BTK Clinical Trial RCT 480 IDE Global Multicenter DCB vs. PTA Safety & Efficacy P. Geraghty J. Mustapha M. Brodmann Caution – Investigational Device, Limited by Federal (USA) Law to Investigational Use
- 7.
- 8. All data fromIN.PACT Amphirion Deep DEB A Brief History of BTK/CLI Data on DCBs
- 9. Leipzig Registry Schmidt etal. JACC 2011;58:1105-9 – Design • Single-Center – N=104 (enrolled Jan 2009-Feb 2010 ) – Procedural Methods • Inflation for ≥ 1 min • In case of 2+ DCBs, balloon overlap = 5mm • Inflow disease treated during same session (n = 28 limbs, proximal PTA) • DAPT for at least 4 weeks post-op – Patient Population • 82.6% with CLI • Mean lesion length= 17.6cm • 55 de novo, 19 restenoses, 10 in-stent-restenoses • Renal Insufficiency = 46.2% • Diabetes = 71.1% • Smoking = 30.8%
- 10. Leipzig Registry Cont’d Schmidtet al. JACC 2011;58:1105-9 – Interventional Success = 100% • 5 bail-out stents placed • Pre-discharge complications = 3 femoral pseudoaneurysms and1 infected diabetic foot – 3-Month follow-up (n=94 patients) • Angiography f/u (n=74 patients) – 72.6% (61/84 arteries) were free of significant restenosis » 61% of restenosis were focal (<20% of initial length) • 3-Month restenosis rate considerably lower than center’s historical data: 27% vs. 69% – No Safety concerns • Amputation rate: 4.4% (typical for population)
- 11. DEBATE-BTK Liistro et al.Circulation 2013;128:615-621 • Study Design • Single-center (Italy), RCT 1:1 • No Core lab • Key Inclusion Criteria: • CLI and diabetes • At least one tibial vessel run-off • Key Exclusion • Allergy to PTX • Life expectancy < 1 year • Primary endpoint: Binary restenosis at 1 year • Secondary Endpoints: 12-Month TLR and 12-Month Occlusion rate
- 12. DEBATE-BTK Cont’d Liistro etal. Circulation 2013;128:615-621 Baseline Demographics DEB PTA P # Lesions 80 78 Diabetes 100% 100% 1 Dialysis 10.8% 10.4% 1 Inflow Treatment 49.2% 52.2% 0.8 Mean Lesion Length (mm) 129 131 0.9 Severe Calcification 25% 28% 0.5 Sub-intimal Recanalization 21.3% 21.8% 0.8 • Procedural Characteristics • 100% Pre-dil in DCB group • Mean inflation time 142 secs • 1 bail-out stent placed (1.3%)
- 13. DEBATE-BTK 1 YearClinical Outcomes Liistro et al. Circulation 2013;128:615-621 1-Year Clinical Outcomes DEB PTA P Death (any cause) 7.7% (5) 4.5% (3) 0.4 Major Amputation 0 1.5% (1) 0.9 Binary Restenosis 27% (20/74) 74.3% (55/74) < 0.001 TLR 15% (12/80) 37% (29/78) 0.002 Complete ulcer healing 86% (56/65) 37% (43/64) 0.01 Authors’ conclusions: “DCBs compared with PTA strikingly reduce 1- year restenosis, TLR and target vessel occlusion in the treatment of BTK lesions in diabetic patients with CLI”
- 14. DEBATE-BTK Two-Year ClinicalOutcomes Liistro LINC 2014 DEB PTA P Death (any cause) 18.5% (12) 16.5% (11) 0.8 Major Amputation 1.4% (1) 2.8% (2) 1 TLR 17.5% (14/80) 41% (32/78) <0.001 Lesions w/ > 1 TLR 2% (2) 11% (9) 0.03 MAE 36% (24) 52% (37 0.05 New restenosis 12-24 months 4 6 Cumulative restenosis 30% (24/80) 78% (61/78 <0.001 Secondary Patency 92% (61/66) 64% (39/61) <0.001 Complete wound healing 93% (53/57) 86% (48/56) Conclusions: • Advantages of DCB observed at 12 months, were maintained at 2 years • Study provides evidence for use of DEB in diabetic patients with CLI
- 15. Challenges of Single-CenterStudies • Mirror’s specific center’s practice • Lower external validity • Limited generalizability • Typically lacks core lab or CEC adjudication • Value in generating hypotheses Rocha-Singh, Review of Clinical Evidence on CLI. LINC 2014 Large, robust studies are essential.
- 16. IN.PACT DEEP Thomas Zeller,LINC 2014 • Study Design – Prospective, multi-center, randomized, – Rigorous execution: independent DCMB, CEC, angiographic and wound core labs, external monitoring with 100% source data verification – N = 358 subjects, enrolled Sep 2009-July 2012 at 13 centers in 6 EU countries – Primary effectiveness endpoints: • Angio Cohort: Late lumen loss at 12 months or time of TLR • All patients: Clinically-driven TLR at 12 months – Primary Safety Endpoint: 6-month all-cause death, major amputation or clinically-driven TLR
- 17. IN.PACT DEEP SelectionCriteria • Key Inclusions • RCC 4,5,6 • Target Vessel: infrapop (including TPT) above ankle • RVD 2-4 mm • At least 1 non-occluded crural vessel w/ run-off to the foot either direct or through collaterals • Single or multiple adjacent lesions (≥70%) with cumulative length of ≤10 cm that can be covered by a single IN.PACT Amphirion DCB • Key Exclusions • Planned major index limb amputation • Inflow impaired or non re-established • Failure to cross the target lesion with a 0.014” guide wire • In-stent-restenosis • Thrombus or aneurysm • GFR < 30ml/min except for patients with ESRD on chronic haemodialysis
- 18. IN.PACT DEEP BaselineCharacteristics DEB PTA P Value Age 73.3 ± 8.2 71.7 ± 9.9 0.106 Male 72.6% 70.6% 0.304 Diabetes 75.7% 68.9% 0.204 Renal Insufficiency (GFR < 30 ml/min) Current Smoker 15.1% 13.4% 0.752 ABI 0.75 0.81 0.264 TBI 0.32 0.46 0.178 RC 5: 84.1% DEB Cohort PTA Cohort RC 5: 77.3% RC 6: 4.2% RC 4: 17.6% RC 3: 0.8% RC 6: 1.7% RC 4: 14.2%
- 19. IN.PACT DEEP BaselineAngiographic Characteristics DEB PTA P Value Lesions 351 181 0.443 Impaired Inflow (≥50%) 40.7% (96/236) 28.8% (34/118) 0.035 Heavy Calcium 13.7% 10.5% 0.332 Moderate Calcium 51.1% 57.5% Target Lesion Length (cm) 10.2 10.9 0.002 Inflation time (secs) 166 137
- 20. IN.PACT DEEP Procedural Characteristics DEBPTA P Value Pre-Dilatation 90.5% 36.0% <0.001 Inflation time (secs) 166 137 0.010 Max Inflation Pressure (atm) 9.5 10.3 0.010 Stenting 3.9% 2.6% 0.446 Procedural complications (excluding post proc. dissections) 9.7% 3.4% 0.035 Post-procedure dissections 12.3% 19.2% 0.046 Device Success1 98% 96.3% 0.224 Procedural success2 98.3% 100% 0.155 1. Device Success: exact deployment of the device according to the IFU as documented with suitable imaging modalities 2. Procedural success: successful vascular access and completion of procedure with ≤ 50% residual stenosis by angio, and device success in the absence of procedural complications.
- 21. IN.PACT DEEP PrimaryOutcomes Primary Efficacy DEB PTA P 12-month LLL (mm) 0.61± 0.78 0.62± 0.78 0.950 12-month Clinically-driven TLR 9.2% (18/196) 13.1% (14/107) 0.291 Primary Safety DEB PTA P 6-month Death, major amputation or Clinically-driven TLR 17.7% (41/232) 15.8% (18/114) 0.021 (non- inferiority) 0.662 (superiority) Did not meet either primary efficacy endpoints
- 22. IN.PACT DEEP SecondaryOutcomes Primary Efficacy DEB PTA P Major Amputation 8.8% (20/227) 3.6% (4/111) 0.080 All-cause Mortality 10.1% (23/227) 8.1% (9/111) 0.551 Death and Amputations 35.2% (80/227) 25.2% (28/111) 0.064 Death, Major Amp, CD TLR 26.9% (61/227) 23.4% (26/111) 0.496 Amputation-Free Survival 81.1% (184/227) 89.2% (99/111) 0.057 Wound Healing (site reported) 73.8% (121/164) 76.9% (70/91) 0.579
- 23. IN.PACT DEEP Conclusions •First large, randomized, level 1 evidence clinical trial of DCB for BTK CLI • Did not meet either primary effectiveness endpoint – PTA outcomes were significantly better than expected • Met the non-inferiority primary safety endpoint • Study findings are limited to BTK CLI indication and IN.PACT Amphirion DEB • Patients will be followed for 5 years
- 24. Where do wego from here?
- 25. Up-coming Level-1 Data •Bard:LEVANT BTK Study • Multi-center, RCT, IDE study • Now enrolling in the US, EU and Japan • N= 480 patients, • randomized 2:1 btwn Lutonix DCB vs. PTA •BEST-CLI Study • NIH-funded, prospective, RCT of 2,100 CLI patients • 5 year follow-up • 80 US and Canadian sites • Enrollment will begin Q2 2014 Rocha-Singh, Review of Clinical Evidence on CLI. LINC 2014
- 26. Trial Summary PRIMARY ENDPOINTS Safetyat 30 days Limb salvage & primary patency at 12 months NUMBER OF PATIENTS/SITES 480 patients at 55 global sites FOLLOW-UP Clinical: 1, 6, 12, 24, and 36 Months Duplex Ultrasound (DUS): 0–30 days, 6,12, 24, & 36 months Angiography in subset of patients: 12 months Telephone: 48 and 60 Months NATIONAL PRINCIPAL INVESTIGATORS Patrick Geraghty: Washington University, St. Louis, MO Jihad Mustapha: Metro Health Hospital, Wyoming, MI Marianne Brodmann: Medical University Graz, Austria SPONSOR Lutonix Inc., Minneapolis, MN Caution – Investigational Device, Limited by Federal (USA) Law to Investigational Use
- 27. Primary Endpoints SAFETY Freedom fromMajor Adverse Limb Events & All-Cause Death at 30 DAYS Amputation (above ankle) Major re-intervention EFFICACY Composite of Limb Salvage and Primary Patency at 12 Months Defined as freedom from the composite of above ankle amputation, target vessel occlusion, and clinically-driven target lesion re-intervention.• New bypass graft • Jump/Interposition graft revision • Thrombectomy/Thrombolysis Caution – Investigational Device, Limited by Federal (USA) Law to Investigational Use
- 28. Patient Eligibility Inclusion Criteria •Male or non-pregnant female ≥18 years of age • Rutherford 4-5 • Life expectancy ≥ 1 year; • Significant stenosis (≥70%) • A patent inflow artery • Target vessel(s) diameter between 2 and 4 mm • Target vessel(s) reconstitute(s) at or above the ankle Exclusion Criteria • Pregnant or planning on becoming pregnant • History of stroke within 3 months • History of MI, thrombolysis or angina within 30 days of enrollment • Prior or planned major amputation • GFR ≤ 30 ml/min per 1.73m2 • Acute limb ischemia • In-stent restenosis of target lesion Caution – Investigational Device, Limited by Federal (USA) Law to Investigational Use
- 29. BTK Trial Design ProtocolFeatures • Randomized 2:1 versus POBA • Permits treatment of two tibial arteries (two flow pathways) • Combined lesion length of up to 32 cm treatable (36 cm balloon length allowed) • Retrograde wire access permitted, but not retrograde intervention • Balloon lengths of up to 12 cm • First U.S. use of tibial patency assessment via duplex ultrasound (VasCore) • Angiographic assessment of normal-risk subset at one year (Synvacor) • Broad range of secondary endpoints including QOL instruments Caution – Investigational Device, Limited by Federal (USA) Law to Investigational Use
- 30. Study Flowchart PTA Pre-Dilatation WithUncoated Balloon Successful PTA with Outflow Randomize 2:1 Test Arm: Dilatation of ALL target lesions with Drug Coated Balloon Control Arm: Dilatation of ALL target lesions with Uncoated Balloon Suboptimal PTA Absence of above ankle reconstitution >75% residual stenosis Treat per standard practice 30 day follow-up for safety Inflow Treatment If needed Caution – Investigational Device, Limited by Federal (USA) Law to Investigational Use
- 31.
- 32. LEVANT 2 PrimaryEndpoints Safety Efficacy Composite of freedom from all-cause peri-operative death & freedom at 1 YEAR in the index limb from: Primary patency of the target lesion at 1 YEAR: • Amputation (above or below the ankle) • Absence of restenosis (defined by DUS PSVR ≥2.5 & freedom from target lesion revascularization (TLR) • Re-intervention • Index-limb-related death
- 33. Major Inclusion Criteria Rutherford2–4 Male or non-pregnant female ≥18 years old Patient is willing to • Consent • Comply with follow up schedule No in-stent restenosis Length ≤15 cm Diameter 4-6 mm ≥70% stenosis CLINICAL CRITERIA ANGIOGRAPHIC CRITERIA
- 34. 6-month Data forRandomized Cohort
- 35.
- 36. Baseline Demographics (ITT) DCBStandard PTA P-value Pooled Age, Mean ± SD (n) 67.8 ± 10.0 (316) 69.0 ± 9.0 (160) 0.207 68.2 ± 9.7 (476) Male gender, % (n/N) 61.1% (193/316) 66.9% (107/160) 0.216 63.0% (300/476) Obesity 34.8% (110/316) 30.6% (49/160) 0.360 33.4% (159/476) Current Smoker 35.1% (111/316) 33.8% (54/160) 0.548 34.7% (165/476) Dyslipidemia 89.6% (283/316) 85.6% (137/160) 0.208 88.2% (420/476) Diabetes 43.4% (137/316) 41.9% (67/160) 0.758 42.9% (204/476) Hypertension 89.2% (282/316) 87.5% (140/160) 0.572 88.7% (422/476) CAD 49.7% (157/316) 48.1% (77/160) 0.748 49.2% (234/476) Rutherford Grade 0.521 2 29.4% (93/316) 34.4% (55/160) 31.1% (148/476) 3 62.7% (198/316) 57.5% (92/160) 60.9% (290/476) 4 7.9% (25/316) 8.1% (13/160) 8.0% (38/476) ABI 0.7 ± 0.2 (306) 0.7 ± 0.2 (156) 0.364 0.7 ± 0.2 (462)
- 37. Lesion/Procedural Characteristics (ITT) DCBStandard PTA P-value Pooled Two lesions treated 1.9% (6/316) 3.1% (5/160) 0.400 2.3% (11/476) Total Lesion Length (mm) 62.9 ± 41.5 (315) 63.6 ± 40.3 (160) 0.866 63.2 ± 41.1 (475) Treated Length (mm) 107.7 ± 47.0 (316) 107.3 ± 49.3 (160) 0.933 107.6 ± 47.7 (476) Calcification 59.2% (187/316) 57.5% (92/160) 0.726 58.6% (279/476) Severe 17.6% (33/187) 13.0% (12/92) 0.326 16.1% (45/279) Total Occlusion 20.6% (65/316) 21.9% (35/160) 0.741 21.0% (100/476) %DS post-treatment 23.4 ± 12.3 (316) 23.8 ± 12.3 (158) 0.703 23.5 ± 12.3 (474) Bail-out Stenting 2.5% (8/316) 6.9% (11/160) 0.022 4.0% (19/476) Dissection 63.7% (200/314) 72.3% (115/159) 0.060 66.6% (315/473) Final Procedural Dissection Grade 0.075 Grade A 59.5% (119/200) 53.9% (62/115) 57.5% (181/315) Grade B 36.5% (73/200) 35.7% (41/115) 36.2% (114/315) Grade C 4.0% (8/200) 10.4% (12/115) 6.3% (20/315) Procedural success (core lab) 88.9% (281/316) 86.8% (138/159) 0.497 88.2% (419/475) Geographic Miss (core lab) 7.9% (24/316) 21.9% (35/160) <0.001 12.6% (60/476)
- 38. Composite Safety Endpoint- KM1 Log-Rank p-value = 0.962 Standard PTA DCB Months Survival DCB PTA Days %[95% CI] %[95% CI] 30 days 99.4% [97.5, 99.8] 99.4% [95.6, 99.9] 183 days 94.0% [90.7, 96.2] 94.1% [88.9, 96.9] FreedomfromPrimarySafetyEvent 1Not pre-specified for hypothesis testing and not adjusted for multiplicity
- 39. Primary Patency -KM1 Months %FreefromPrimaryPatencyEvent Survival DCB PTA Days %[95% CI] %[95% CI] 30 days 99.7% [97.8, 100.0] 100.0% [N/A] 183 days 92.3% [88.6, 94.8] 82.7% [75.6, 87.8] Standard PTA DCBLog-Rank p-value = 0.003 1Not pre-specified for hypothesis testing and not adjusted for multiplicity
- 40. Primary Patency –12 Mo
- 41. Other Secondary Endpointsat 6 Months1 Measure DCB % (n/N) PTA % (n/N) Difference2 P-value2 Binary Restenosis 17.4% (47/270) 33.8% (47/139) -16.4% <0.001 Composite Safety Endpoint Failure 8.0% (24/299) 8.6% (13/151) -0.6% 0.016 (non-inferiority) TVR 6.7% (20/298) 7.9% (12/151) -1.2% 0.633 Death 0.7% (2/301) 1.3% (2/152) -0.7% 0.497 Amputation 0.3% (1/299) 0.0% (0/151) 0.3% 0.366 Embolization (any during index procedure) 0.6% (2/316) 1.9% (3/160) -1.2% 0.226 Re-intervention for Thrombosis or Embolism (target vessel) 0.3% (1/298) 0.7% (1/151) -0.4% 0.623 1Proportions through close of 6-month follow-up window (212 days) 2Not pre-specified for hypothesis testing and not adjusted for multiplicity
- 42. Walking Impairment Questionnaire 0 10 20 30 40 50 60 70 80 WIQTotal Score Walking Distance Score Walking Speed Score Stair Climbing Score RawScore DCB Baseline DCB 6 Months PTA Baseline PTA 6 Months 1Not pre-specified for hypothesis testing and confidence intervals not adjusted for multiplicity 2Combined score is calculated as the mean of the distance, speed, and stair scores. Change From Baseline1 DCB-PTA Difference % (95% CI) WIQ Total Score2 6.0% (0.1, 12.0) Walking Distance Score 7.6% (0.1, 15.2) Walking Speed Score 4.3% (-1.9, 10.5) Stair Climbing Score 6.7% (-0.2, 13.5) 2
Editor's Notes
- #3 So how do we treat PAD once it’s diagnosed? This slide depicts Covidien’s treatment philosophy, which we refer to as the PAD Continuum of Care. It shows the progression of treatment options from least invasive on the left – beginning with a healthy leg and screening, -- and ends on the right with the most invasive treatment – loss of leg through amputation. Ultimately, the goal is to save the patient’s life, but the importance of preserving quality of life by saving the leg cannot be underestimated. The farther one moves to the right on the treatment continuum, the more irreversible the treatment becomes, limiting long-term treatment options. While PAD can be treated, it cannot be cured. As such, patients entering the hospital system for PAD will likely require reintervention after each stage of treatment, as well as additional management of the co-morbidities linked to PAD. As such, we believe that using the least invasive treatment options as the first line of treatment will help preserve the native vessel, thereby keeping more treatment options open for PAD patients.
- #7 Bard/Lutonix is investing in rigorous clinical studies in PAD to expand and refine treatment options and indications. CLI patients face poor clinical outcomes with existing treatments and DCB is a viable option. Lutonix DCB provides an innovative, state of the art solution for treating BTK/CLI patients that delivers an optimal amount of drug to the diseased vessel while minimizing systemic and downstream exposure.
- #9 The first BTK study published was a single-center registry with 3 month data that compared favorably to the center’s historical PTA data from a similar patient population. During this time, the DEBATE BTK and In.PACT DEEP studies were enrolling patients. The DEBATE BTK results were published in June 2013. This was a randomized study with 12 month results, which were also positive. And then in December, Medtronic recalled their BTK DCB based on outcomes from the IN.PACT deep study that were just presented at LINC on Jan 30th. In the next few slides, I will go over these study designs and outcomes. It is critical to remember that all of these studies were conducted with the Amphirion Deep DEB. There is no class effect with DCBs. The pharmacological properties, such as absorption and distribution, of the drug are determined by the coating and the manufacturing process. (reference: Schnorr 2013)
- #12 24 month data presented at LINC 2014 (Liistro)
- #13 Enrollment from Nov 2010- Oct 2011 N= 132 patients Multi-disciplinary follow-up Office visits scheduled 2x/ week for the first 2 months and then 1x/week for the third month and then once every 2 weeks thereafter
- #24 “Safety signal towards major amputations, in conjunction with the absence of significant efficacy, let to market withdrawal
- #25 More rigorous data are required. There are currently 2 more DCB CLI trials still in the early stages.