Доклад Натальи Востоковой, Исполнительного директора ИФАРМА, на международной конференции DIA 2016 28 Annual EuroMeeting в Гамбурге.

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Adaptive design in dose selection
studies of next-in-class drugs
Natalia Vostokova
Chief Operating Officer
IPHARMA LLC

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Background
Adaptive clinical trial design refers to studies that allow modifying
any design or hypothesis aspect based on the interim data
analysis.
Any adaptation is appropriate solely in accordance with the
predefined plan and at preselected time points.
Although adaptation in dose selection studies are still considered
less understood, its methodology can be successfully introduced
in clinical programs of next-in-class drugs.
© 2015 DIA, Inc. All rights reserved.

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Next-in-class drugs
Next-in-class drugs are original patented medications with known
targets similar to existing drugs in structure and mode of action.
Strengths:
• abundant clinical data available for medications of the same class
• higher predictability of drug effects in humans
• possible achievement of better clinical results
Opportunities:
• predictable endpoints
• non-inferiority hypothesis
• accurate sample size calculation
• well-studied control
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Direct factor Xa inhibitors
Indication:
• prevention and treatment of thromboembolism (VTE)
• non-valvular atrial fibrillation
• hip and knee replacement surgery
Clinical model in Phase 2:
• VTE prevention in total knee replacement surgery
First-in-class:
• Rivaroxaban, Apixaban
© 2015 DIA, Inc. All rights reserved.

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Objective
Adaptive two-stage design with interim analysis for dose
selection in Phase 2 study of new factor Xa inhibitor TeaRxaban.
The study objectives:
1. To select the optimal dose of TeaRxaban, and
2. To evaluate its efficacy and safety vs. Enoxaparin in VTE
prevention following total knee replacement
© 2015 DIA, Inc. All rights reserved.

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Method
Multicenter randomized partially blinded clinical trial of
TeaRxaban at 7 Russian sites.
TeaRxaban 50, 100, and 150 mg was studied at Stage 1.
Optimal dose was selected using Simon’s Minimax approach.
Additional patients were enrolled at Stage 2 and non-inferiority
(5% margin) of TeaRxaban vs. Enoxaparin was tested.
© 2015 DIA, Inc. All rights reserved.

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Adaptive design
© 2014 DIA, Inc. All rights reserved.

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Screening Randomization TKR In-patient treatment Out-patient follow-up
Day D-14…-1 D0 D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D12 (EOT) D21 D42
Week W-2 W0 W1 W3 W6
- TeaRxaban ХХ mg (first dosing > 10 hours after the surgery)
Enoxaparin 40 mg s.c. (first dosing on the eve of the surgery) -
Study treatment
The primary efficacy endpoint total VTE was composite of
confirmed DVT, non-fatal PE and all-cause mortality during 6
weeks following total knee replacement.
Safety endpoints included incidence of major and clinically
relevant non-major bleeding.
© 2015 DIA, Inc. All rights reserved.

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Analysis: Stage 1
Efficacy: VTE (including DVT,
non-fatal PE and all case
mortality)
Safety: major and clinically
relevant non-major bleeding
© 2014 DIA, Inc. All rights reserved.
Drugs Dose Patients
TeaRxaban 50 mg 5/21 23.8%
TeaRxaban 100 mg 3/21 14.3%
TeaRxaban 150 mg 1/20 5.0%
Enoxaparin 40 mg 5/22 22.7%
Drugs Dose Patients
TeaRxaban 50 mg 2/21 9.5%
TeaRxaban 100 mg 0/21 0.0%
TeaRxaban 150 mg 1/21 4.8%
Enoxaparin 40 mg 1/22 4.5%

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Analysis: Stage 2
Efficacy: VTE (including DVT,
non-fatal PE and all case
mortality)
Safety: major and clinically
relevant non-major bleeding
© 2014 DIA, Inc. All rights reserved.
Drugs Dose Patients
TeaRxaban 100 mg 14/73 19.2%
Enoxaparin 40 mg 21/76 27.6%
Drugs Dose Patients
TeaRxaban 100 mg 0/73 0.0%
Enoxaparin 40 mg 2/76 2.6%
∆ -8.45% [-19.59%; 3.01%]
Right bound of 95%CI < 5%

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Analysis: Stage 2
Safety: Adverse Events Safety: Serious Adverse
Events
© 2014 DIA, Inc. All rights reserved.
Drugs Dose Patients
TeaRxaban 100 mg 21/73 28.8%
Enoxaparin 40 mg 33/76 43.4%
Drugs Dose Patients
TeaRxaban 100 mg 2/73 2.7%
Enoxaparin 40 mg 5/76 6.6%

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Conclusion
Adaptive design in Phase 2 dose selection studies
• significantly smaller sample size
• choice of optimal dose based on interim analysis
• shorter timelines for testing the non-inferiority versus standard of care
Control of potential biases
• independent central assessment of efficacy and safety endpoints.
• no changes to the initial statistical assumption and methods
Justified and tailored adaptive design can be recommended for
clinical development of next-in-class drugs.
© 2014 DIA, Inc. All rights reserved.

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Authors
IPHARMA LLC (CRO in Russia and EAEU)
• Natalia Vostokova, PharmD, Chief Operating Officer
• Julia Trakhtenberg, MD, PhD, Medical Director
• Natalia Krivonos, PhD, PM, Project Manager
National Medical and Surgery Center n.a. N.I. Pirogov
• Mikhail Zamyatin, MD, PhD, Professor
Contact information:
• Mob. +7 (926) 098 36 33
• E-mail: nv@ipharma.ru
• Web: www.ipharma.ru
© 2015 DIA, Inc. All rights reserved.