Доклад «Адаптивный дизайн исследования по подбору дозы нового препарата класса прямых ингибиторов

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Adaptive design in dose selection studies of next-in-class drugs

Natalia VostokovaChief Operating OfficerIPHARMA LLC

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Disclaimer

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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


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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, and2. To evaluate its efficacy and safety vs. Enoxaparin in VTE

prevention following total knee replacement


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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.


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Adaptive design


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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.


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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


Drugs Dose Patients

TeaRxaban 50 mg 5/21 23.8%



Enoxaparin 40 mg 5/22 22.7%

Drugs Dose Patients





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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


Drugs Dose Patients

TeaRxaban 100 mg 14/73 19.2%


Drugs Dose Patients



∆ -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


Drugs Dose Patients

TeaRxaban 100 mg 21/73 28.8%


Drugs Dose Patients



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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.


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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: [email protected]• Web: www.ipharma.ru


mailto:[email protected]

mailto:[email protected]

http://www.ipharma.ru/

Health & Medicine

Доклад «Адаптивный дизайн исследования по подбору дозы нового препарата класса прямых ингибиторов