Statistical Considerations for an Adaptive Design for a Serious Rare Disease Gary R Cutter, PhD On behalf of Kaushik Patra, PhD, Bruce A.C. Cree, Eliezer Katz, Erik Pulkstenis, Alex Dmitrienko, and myself (authors of this paper)

Neuromyelitis optica (NMO) and Neuromylelitis Optica Spectrum Disorder (NMOSD) Acute/subacute demyelination, necrosis of optic nerves, spinal cord Primarily in females (9 to 1) Often preceded by viral illness, associated with systemic autoimmune disease Significant residua common Partial responses to steroids, other immunosuppressants The term NMOSD reflects a variety of disorders associated with anti-AQP4 antibodies thought to be related to NMO but do not quite fit the diagnostic criteria for definite NMO. This includes brainstem disorder with clinical features including intractable hiccups and nausea, or vomiting

NMO and NMOSD NMO/NMOSD prevalence is estimated to be between 0.5 and 4.4/100,000 To date, no randomized controlled clinical studies of NMO have been completed No treatment has received regulatory approval

Diagnosis of NMOSD All 3 findings are required: Optic neuritis Transverse myelitis 2 of 3 of the following supportive criteria: Contiguous cord lesion involving more than 3 vertebral segments Anti-aquaporin-4 IgG seropositivity Brain MRI not meeting criteria for Multiple Sclerosis

Treating NMOSD One area of controversy within the NMOSD community and among regulatory agencies is the appropriateness of a placebo-controlled design in this disease. Although placebo control can provide unequivocal evidence of efficacy, there is a legitimate concern about not treating patients Untreated subjects may be at higher risk of relapses (and their consequences) Can be fatal

Treatments For NMOSD Immunosuppressive medications such as: azathioprine, mycophenolate mofetil, mitoxantrone, prednisone, and rituximab are all used empirically to prevent attacks the evidence to support their use is limited, but are widely viewed by clinicians as worthwhile Either because of positive experience Or because it allows them to do something

Design and Statistical Aspects Considered in an NMOSD Trial 1. Determination of the primary endpoint 2. Choice of comparator and design consideration 3. Stratification, randomization ratio, and sample size calculation 4. Interim analyses 5. Secondary endpoints and multiplicity adjustment 6. Ethical considerations 7. Assessment of primary endpoint, adjudication process and related analyses strategies MediImmune Trial: A Double-masked, Placebo-controlled Study With Open Label Period to Evaluate MEDI-551 in Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorders NCT02200770

Determination of the primary endpoint Given that sometimes NMOSD relapses cause irreversible disability, the occurrence of a single relapse on treatment has been accepted by investigators and regulatory agencies to be a primary outcome. Clinically relevant criteria for each of the typical NMO types of relapse were developed by expert consensus: for optic neuritis (11 criteria) myelitis (4 criteria) brain stem (2 criteria), and hemispheric events (1 criterion). A central committee is responsible for adjudicating each relapse to be used for the primary endpoint.

Choice of comparator and design consideration Could a placebo be used? Great debate on this topic A single relapse event with rescue was considered adequate to balance the FDA preference for a placebo, while respecting the clinicians unease Minimize the exposure to placebo Use 3 to 1 randomization

How Long on a Placebo is Tolerable? The traditional time-to-event designs follow patients on their treatment assignment until a specified number of medically relevant events have accrued. This strategy was not tenable for the current study because indefinite placebo exposure was considered to potentially be an excessive burden or risk for the study subjects. Therefore the duration of follow up was truncated.

A time-to-event design (Figure 1) with each patient on the randomized controlled treatment for a maximum of 197 days (approximately 7 months) or until an NMOSD relapse occurred (whichever occurred first).

In order to protect the subjects from further worsening as a consequence of NMOSD relapses, immediate rescue treatment with high-dose steroids, plasmapheresis or intravenous immunoglobulin (interventions commonly used to treat NMOSD relapses) were incorporated into the study.

Stratification, Randomization Ratio, and Sample Size Calculation Since not all NMOSD are AQP4+ Expected rate of AQP4+ of 4 to 1 seronegative patients may have lower relapse rates – but not assumed for overall analyses stratification by antibody positivity was deemed appropriate Sample size estimates were based on pooled non-randomized trials to estimate the number of events needed and the placebo hazard rate was calculated as the negative logarithm of the proportion of relapse-free subjects over the first 12 months between the first two relapses prior to treatment from historical data.

From Costanzi C, Matiello M, Lucchinetti CF, et al. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology. 2011;77:659-666.

Effect of Therapy The weighted average of the hazard rates (previous Table 1) for rituximab and azathioprine treated subjects was calculated as 0.25 and 0.58 per year, respectively. Rituximab at 0.25 is a B-cell treatment and MEDI-551 is also a B-cell therapy From this evidence, a conservative estimate of HR 0.40 was hypothesized and an acceptable target efficacy of MEDI-551 against placebo.

Sample Size Determined by Simulation* The study was powered for the ITT population while protecting the power in seropositive cohort *Simulation results from 5000 iterations.

Expected Events Calculated as: and

No Planned Interim Efficacy Analyses (1) the target treatment effect is optimistic; (2) the required number of events is relatively small; (3) enrichment of the safety database for the experimental drug will be impaired; (4) integrity of the adjudication process around the primary endpoint may not be fully evaluable, potentially impacting regulatory review; (5) assessment of secondary objectives will be impaired; and (6) by design, all subjects eventually will be treated with MEDI-551 without an early efficacy claim.

Masked Sample Size Re-estimation The fundamental theme of this method lies around re-estimating the survival probability based on the observed Kaplan-Meier failure rate (both treatments combined) at an interim time point. Using the re-estimation approach of Todd et.al * estimation based on the average difference was used to find the adjustment factor. * Todd S, Valdes-Marquez E, West J. A practical comparison of blinded methods for sample size reviews in survival data clinical trials. Pharm Stat. 2012;11:141-148)

At the Interim SS Re-assessment We compute Suppose φ = 0.112 and 104 subjects have completed the trial (relapsed or censored), then working through the previous equations we obtain: Snew will be 0.734 (note SD = 0.67) and subsequently Nnew becomes 252, an increase of 40 subjects. If the observed event to subject ratio is approximately 27%= (1-Snew)% when 104 subjects complete the trial portion, an increase in target sample size up to 252 subjects will be considered to preserve the statistical power at approximately 94%, assuming a 4:1 ratio is maintained in seropositive versus sero-negative cohorts.

Potential Changes in Sample Size

Futility Assessment Futility is to be assessed based on conditional power expressed by:

While fewer relapses are required to establish efficacy with placebo as the control compared to an active comparator with known efficacy – above the fewer relapses are achieved by assuming a larger effect of the treatment, not unreasonable for comparison with a placebo.

Unequal Versus Equal Allocation A two-sided test of whether the hazard ratio is one with an overall sample size of 350 subjects (of which 175 are in the control group and 175 are in the treatment group) achieves 90% power at a 0.050 significance level when the hazard ratio is actually 0.500. The number of events required to achieve this power is 88 (87.5) Unequal Allocation A two-sided test of whether the hazard ratio is one with an overall sample size of 468 subjects (of which 117 are in the control group and 351 are in the treatment group) achieves 90% power at a 0.050 significance level when the hazard ratio is actually 0.500. The number of events required to achieve this power is 117 Thus, from a societal perspective almost 33% more patients experience events than in the placebo controlled trial

Active Versus Placebo Comparator Placebo Controlled with 50% reduction A two-sided test of whether the hazard ratio is one with an overall sample size of 350 subjects (of which 175 are in the control group and 175 are in the treatment group) achieves 90% power at a 0.050 significance level when the hazard ratio is actually 0.500. The number of events required to achieve this power is 87.5. A two-sided test of whether the hazard ratio is one with an overall sample size of 1322 subjects (of which 661 are in the control group and 661 are in the treatment group) achieves 90% power at a 0.050 significance level when the hazard ratio is actually 0.700. The number of events required to achieve this power is 330.5. Thus, from a societal perspective almost 4 times as many patients experience events than in the placebo controlled trial

Additional Topics in the Paper We touch on multiplicity of testing given the stratification of seropositivity argue for strong control on the assessments with the power placed on the larger subgroup (seropositive =80% of the population) We discuss and provide examples of the impact of the adjudication committee, based mostly on the concept that noise biases toward the null. This is more important in noninferiority trials where non-adjudicated results may bias away from the null, but also relevant in rare diseases where finding patients is difficult

Conclusions Rare serious diseases present two problems Small available sample Often reluctance to use a placebo A series of underpowered studies is not the answer While not optimal from a statistical perspective N to 1 matching may be preferred to 1 to 1 matching from the clinical perspective.

Conclusions Continued Limiting exposure time can be an acceptable approach when the events occur reasonably rapidly to minimize exposure to placebos With almost all rare diseases precision of the estimates for planning may be less than adequate thus blinded sample size adjustments may be worthwhile in these instances The feasibility with smaller effect sizes needs to be examined in the context of the disease under consideration

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