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Adaptive Design in Dose Selection Study of Next-in-Class NNRTI

Natalia Vostokova, PharmDChief Operating OfficerIPHARMA LLC

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Disclaimer

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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 adaptations in dose selection studies are still considered less understood, the methodology can be successfully introduced in clinical programs of next-in-class drugs.

Background

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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 comparator

Next-in-class drugs

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Non-nucleoside reverse-transcriptase inhibitors– First generation: Efavirenz, Nevirapine

– Next generation: Etravirine, Rilpivirine

In combination with HAART (2 NRTI or Protease inhibitor + NRTI)

Safety issues– Psychiatric symptoms (depression, suicidal ideation, aggressive behavior, etc.)

– Nervous system symptoms (dizziness, insomnia, impaired concentration, etc.)

– Rash and allergic reactions

NNRTI in HIV treatment

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Adaptive two-stage design with interim analysis for dose selection in Phase 2-3 study of new NNRTI Elpivirine

The study objective:

1. To select the optimal dose of Elpivirine, and

2. To evaluate its efficacy and safety vs. Efavirenz in combination with 2 NRTI in treatment naïve patients with HIV

Objective

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Design: Multicenter randomized partially-blinded two-stage clinical trial.

Population: Treatment-naïve patients with HIV

Groups: Elpivirine 20 mg, Elpivirine 40 mg and Efavirenz 600 mg

Stage 1: Optimal dose of Elpivirine was selected based on viral load at Week 12.

Stage 2. Additional patients were enrolled and non-inferiority of Elpivirine (selected dose) vs. Efavirenz was tested.

Method

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Interim analysis based on surrogate endpoint No statistical adjustments or hypothesis changes during the study

Adaptive “seamless” Phase 2-3 design

Elpivirine 20 mg30 patients

-->Elpivirine 20 mg

+ 30 patients

________Elpivirine 40 mg

30 patients --> X

Efavirenz 600 mg30 patients

-->Efavirenz 600 mg

+ 30 patients

Treatment-naïve patients with HIV

(150 patients)

Interim analysis(Non-inferiority at Week 12)

Final analysis(Non-inferiority at Week 24)

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Primary efficacy endpoint– Stage 1: Decrease of viral load <400 copies/ml by Week 12 (% pts) – Stage 2: Decrease of viral load <50 copies/ml by Week 24 (% pts)

Secondary endpoints– Efficacy: viral load change during 48 weeks of treatment, ≥1 Log10 viral

load decrease by Week 4, change of CD4+ and CD8+, drug resistance mutations

– Safety: AE, AE of Special Interest (CNS)

Study endpoints

Screening Randomi-zation

Stage 1 Endpoint

Stage 2 Endpoint

End of treatment

Follow-up

W-2 W0 W4 W12 W18 W24 W36 W48 W52

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Efficacy: % patients who achieved < 400 copies/ml by Week 12

Safety: AE and AE of Special Interest (CNS)

Interim Analysis: Stage 1

Elpivirine 20 mgn (%)N=30

Elpivirine 40 mgn (%)N=29

Efavirenz 600 mgn (%)N=27

% patients 28 (93.3%) 25 (86.2%) 22 (81.5%)

∆  11.85%   4.73%  

[95% CI] [-2.6; 26.9] [-11.5; 20.8]

Lower bound of 95% CI > -15% (NI margin) in both groups

Elpivirine 20 mg

n (%) / AEN=30

Elpivirine 40 mg

n (%) / AEN=29

Efavirenz 600 mg

n (%) / AEN=28

AE 21 (70.0%) / 124 25 (86.2%) / 209 24 (85.7%) / 275

Related 8 (26.6%) / 43 20 (69.0%) / 123 20 (71.4%) / 219

AEOI 8 (26.7%) / 35 13 (44.8%) / 50 16 (57.1%) / 145

DMC selected Elpivirine 20 mg for Stage 2.Study results are expected by the end of

2016

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Additional 60 patients have been enrolled in the study according to the protocolThe primary efficacy endpoint will be assessed in 120 patients:

The final study analysis including the primary efficacy endpoint (% of patients who achieved < 50 copies/ml by Week 24) is expected by the end of 2016

Stage 2

Group Stage 1 Stage 2 TotalElpivirine 20 mg 30 + 30 = 60

patientsEfavirenz 600 mg 30 + 30 = 60

patients

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Adaptive “seamless” Phase 2-3 design – significantly smaller sample size than in two consecutive studies

– choice of optimal dose based on interim analysis of a surrogate endpoint

– 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

Conclusion

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Natalia Vostokova, PharmDChief Operating OfficerIPHARMA LLC CRO in Russia and EAEUnv@ipharma.ru

CO-AUTHORS:Prof. Alexey Kravchenko, MD, PhD, Russian Federal AIDS Centre, Central Research Institute of EpidemiologyVadim Bychko, PhD, Viriom LLCOlga Alyoshina, MD, PhD, Viriom LLCOlga Zozulya, MD, PhD, IPHARMA LLC

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