Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient-level placebo (Standard-of-Care) data to enable model-informed drug development.

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems. Many investigational agents have failed or shown only modest effects when added to standard of care (SoC) therapy in placebo-controlled trials, and only two therapies have been approved for SLE in the last 60 years. Clinical trial outcomes have shown discordance in drug effects between clinical endpoints. Herein, we characterized longitudinal disease activity in the SLE population and the sources of variability by developing a latent disease trajectory model for SLE component endpoints (Systemic Lupus Erythematosus Disease Activity Index [SLEDAI], Physician's Global Assessment [PGA], British Isles Lupus Assessment Group Index [BILAG]) and composite endpoints (Systemic Lupus Erythematosus Responder Index [SRI], BILAG-based Composite Lupus Assessment [BICLA], and Lupus Low Disease Activity State [LLDAS]) using patient-level historical SoC data from nine phase II and III studies. Across all endpoints, in predictions up to 52 weeks from the final disease trajectory model, the following baseline covariates were associated with a greater decrease in SLE disease activity and higher response to placebo + SoC: Hispanic ethnicity from Central/South America, absence of hypocomplementemia, recent SLE diagnosis, and high baseline disease activity score using SLEDAI and BILAG separately. No discernible differences were observed in the trajectory of response to placebo + SoC across different SoC medications (antimalarial and immunosuppressant such as mycophenolate, methotrexate, and azathioprine). Across all endpoints, disease trajectory showed no difference in Asian versus non-Asian patients, supporting Asia-inclusive global SLE drug development. These results describe the first population approach to support a model-informed drug development framework in SLE.

A randomized, double-blind, placebo-controlled phase 1 study of multiple ascending doses of subcutaneous M1095, an anti-interleukin 17A/F nanobody, in moderate-to-severe psoriasis.

BACKGROUND: Interleukin 17 is involved in the pathogenesis of psoriasis, a chronic debilitating disease. OBJECTIVES: To evaluate the safety/tolerability, immunogenicity, pharmacokinetics/pharmacodynamics, and efficacy of M1095, an anti-interleukin 17A/F nanobody, in moderate-to-severe plaque psoriasis. METHODS: This multicenter, double-blind, placebo-controlled dose escalation phase 1 study randomized 44 patients 4:1 to treatment with subcutaneous M1095 (30, 60, 120, or 240 mg) or placebo biweekly for 6 weeks, in 4 ascending dose cohorts. RESULTS: The most frequent treatment-emergent adverse events with M1095 were pruritus (n = 4) and headache (n = 3); 2 patients withdrew owing to adverse events (injection site reaction and elevated liver enzyme levels). The terminal half-life of M1095 was 11 to 12 days. The area under the curve/maximum concentration was dose proportional. Of 10 M1095-treated patients positive for antidrug antibodies, 5 showed treatment-emergent antidrug antibody responses. There was no effect on M1095 exposure. Marked decreases in psoriasis inflammatory markers were observed with M1095. By day 85, 100% and 56% of patients receiving M1095, 240 mg, achieved psoriasis area and severity index 90 and 100, respectively. Improvements in static Physician's Global Assessment and affected body surface area were also seen. LIMITATIONS: Interpretation of efficacy data is limited by the small sample size. CONCLUSION: Multiple subcutaneous doses of M1095 showed a favorable safety profile with dose-dependent improvements in psoriasis.

Factors influencing long-term outcomes in relapsing-remitting multiple sclerosis: PRISMS-15.

AIM: An exploratory study of the relationship between cumulative exposure to subcutaneous (sc) interferon (IFN) ß-1a treatment and other possible prognostic factors with long-term clinical outcomes in relapsing-remitting multiple sclerosis (RRMS). METHODS: Patients in the original PRISMS study were invited to a single follow-up visit 15 years after initial randomisation (PRISMS-15). Outcomes over 15 years were compared in the lowest and highest quartile of the cumulative sc IFN ß-1a dose groups, and according to total time receiving sc IFN ß-1a as a continuous variable per 5 years of treatment. Potential prognostic factors for outcomes were analysed. RESULTS: Of 560 patients randomised in PRISMS, 291 returned for PRISMS-15 and 290 (51.8%) were analysed. Higher cumulative dose exposure and longer treatment time appeared to be associated with better outcomes on: annualised relapse rate, number of relapses, time to Expanded Disability Status Scale (EDSS) progression, change in EDSS, proportions of patients with EDSS ≥ 4 or ≥ 6, ≤ 5 relapses and EDSS <4 or <6, and time to conversion to secondary-progressive MS (SPMS). Higher dose exposure was associated with lower proportions of patients with EDSS progression and conversion to SPMS, and longer time on treatment with lower risk of first relapse. Change in EDSS from baseline to 24 months was a strong predictor of evaluated clinical outcomes over 15 years. CONCLUSIONS: These findings suggest that higher cumulative exposure to sc IFN ß-1a may be associated with better clinical outcomes, and early change in EDSS score may have prognostic value, over many years, in RRMS.

Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial.

BACKGROUND: Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS. METHODS: Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985. FINDINGS: Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, p<0.0001; HR for 3.5 mg/kg=0.33, 0.21-0.51, p<0.0001). Adverse events were reported in 165 (81%) patients in the cladribine 5.25 mg/kg group, 168 (82%) patients in the cladribine 3.5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group. INTERPRETATION: Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS. FUNDING: Merck Serono SA Geneva, a subsidiary of Merck KGaA, Darmstadt, Germany.

Patient subgroup analyses of the treatment effect of subcutaneous interferon ß-1a on development of multiple sclerosis in the randomized controlled REFLEX study.

The REFLEX study (NCT00404352) established that subcutaneous (sc) interferon (IFN) ß-1a reduced the risks of McDonald MS (2005 criteria) and clinically definite multiple sclerosis (CDMS) in patients with a first clinical demyelinating event suggestive of MS. The aim of this subgroup analysis was to assess the treatment effect of sc IFN ß-1a in patient subgroups defined by baseline disease and demographic characteristics (age, sex, use of steroids at the first event, classification of first event as mono- or multifocal, presence/absence of gadolinium-enhancing lesions, count of <9 or ≥9 T2 lesions), and by diagnosis of MS using the revised McDonald 2010 MS criteria. Patients were randomized to the serum-free formulation of IFN ß-1a, 44 µg sc three times weekly or once weekly, or placebo, for 24 months or until diagnosis of CDMS. Treatment effects of sc IFN ß-1a on McDonald 2005 MS and CDMS in the predefined subgroups were similar to effects found in the intent-to-treat population. McDonald 2010 MS was retrospectively diagnosed in 37.7 % of patients at baseline. Both regimens of sc IFN ß-1a significantly reduced the risk versus placebo of McDonald 2005 MS and CDMS, irrespective of McDonald 2010 status at baseline (risk reductions between 29 and 51 %). The effect of sc IFN ß-1a was not substantially influenced by baseline patient demographic and disease characteristics, or baseline presence/absence of McDonald 2010 MS.

Efficacy of subcutaneous interferon ß-1a on MRI outcomes in a randomised controlled trial of patients with clinically isolated syndromes.

AIM: The REbif FLEXible dosing in early MS (REFLEX) study compared several brain MRI outcomes in patients presenting with clinically isolated syndromes suggestive of multiple sclerosis and treated with two dose-frequencies of subcutaneous interferon (IFN) ß-1a or placebo. METHODS: Patients were randomised (1:1:1) to IFN ß-1a, 44 µg subcutaneously three times a week or once a week, or placebo three times a week for up to 24 months. MRI scans were performed every 3 months, or every 6 months if the patient developed clinically definite multiple sclerosis. End points analysed included: number of combined unique active lesions per patient per scan; numbers and volumes of new T2, T1 hypointense and gadolinium-enhancing (Gd+) lesions per patient per scan; and brain volume. RESULTS: 517 patients were randomised (intent-to-treat population: subcutaneous IFN ß-1a three times a week, n=171; subcutaneous IFN ß-1a once a week, n=175; placebo, n=171). Combined unique active lesions were lower in patients treated with subcutaneous IFN ß-1a versus placebo (mean (SD) lesions per patient per scan: three times a week 0.6 (1.15); once a week 1.23 (4.26); placebo 2.70 (5.23); reduction versus placebo: three times a week 81%; once a week 63%; p<0.001) and with three times a week versus once a week (48% reduction; p=0.002). The mean numbers of new T2, T1 hypointense and Gd+ lesions were all significantly lower in the two active treatment arms compared with placebo (p≤0.004 for three times a week or once a week) and in the three times a week group compared with once a week (p≤0.012). CONCLUSIONS: Both subcutaneous IFN ß-1a 44 µg regimens improved MRI outcomes versus placebo, with the three times a week regimen having a more pronounced effect than once a week dosing. TRIAL REGISTRATION: clinicaltrial.gov identifier, NCT00404352.

Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial.

BACKGROUND: In patients presenting with a first clinical demyelinating event that is suggestive of multiple sclerosis (MS), treatment with interferon beta can delay the occurrence of further attacks and the onset of MS. We investigated the effects of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event. METHODS: We undertook a multicentre phase 3 study (REbif FLEXible dosing in early MS [REFLEX]) that included patients (aged 18-50 years) with a single clinical event suggestive of MS, and at least two clinically silent T2 lesions on brain MRI. Participants were randomly assigned in a 1:1:1 ratio by use of a centralised interactive voice response system to receive the serum-free formulation of subcutaneous interferon beta-1a 44 µg three times a week or once a week (plus placebo twice a week for masking), or placebo three times a week for up to 24 months. Patients and physicians were masked to group allocation. The primary endpoint was time to a diagnosis of MS as defined by the 2005 McDonald criteria and the main secondary endpoint was time to clinically definite MS (CDMS) as defined by the Poser criteria. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00404352. FINDINGS: 517 patients were randomly assigned (171 to subcutaneous interferon beta-1a three times a week, 175 to subcutaneous interferon beta-1a once a week, and 171 to placebo) and 515 were treated. The 2-year cumulative probability of McDonald MS was significantly lower in patients treated with subcutaneous interferon beta-1a (three times a week 62·5%, p<0·0001, hazard ratio [HR] 0·49 [95% CI 0·38-0·64]; once a week 75·5%, p=0·008, HR 0·69 [0·54-0·87]) versus placebo (85·8%). 2-year rates of conversion to CDMS were lower for both interferon beta-1a dosing regimens (three times a week 20·6%, p=0·0004, HR 0·48 [0·31-0·73]; once a week 21·6%, p=0·0023, HR 0·53 [0·35-0·79]) than for placebo (37·5%). Adverse events were within the established profile for subcutaneous interferon beta-1a. INTERPRETATION: Both regimens of subcutaneous interferon beta-1a delayed clinical relapses and subclinical disease activity. The potential differences between the regimens warrant longer-term study. FUNDING: Merck Serono SA, Geneva, Switzerland.

Analytical approaches to reporting long-term clinical trial data.

BACKGROUND AND SCOPE: Long-term clinical studies are essential for monitoring the effectiveness and safety of a drug. Information provided by long-term clinical studies complements the results of short-term, randomized, controlled trials, which often form the basis of regulatory approval for a new drug application. As the duration of a study increases and the number of patients continuing in the study declines, missing data become more of a problem: they may bias the results. Therefore, standard analytical strategies used in short-term randomized, controlled trials (intent-to-treat, per-protocol) may not always be appropriate for data generated in long-term studies. OBJECTIVE: To review commonly used analytical approaches in the assessment of clinical trial data and to identify and address issues related to these approaches in the analysis of long-term study data. FINDINGS: The authors suggest the use of an intent-to-observe population in long-term studies, applying at least three different analytical methods for handling missing data, testing for bias as a sensitivity analysis and reporting results of more than one method if they differ from one another. LIMITATIONS: Statistical approaches to data analysis are not addressed in this review. CONCLUSION: The use of multiple analyses is supported by regulatory authority and expert guidelines, although it has not been widely adopted in the medical literature. Given the inherent limitations of accounting for missing data with each method, the multiple-analysis approach provides more information with which to make better informed decisions, and clearly defined multiple analytical methods may prevent misleading conclusions from being drawn.

Immunogenicity and tolerability of an investigational formulation of interferon-beta1a: 24- and 48-week interim analyses of a 2-year, single-arm, historically controlled, phase IIIb study in adults with multiple sclerosis.

BACKGROUND: RNF (Rebif New Formulation, Merck Serono International S.A., Geneva, Switzerland), a formulation of interferon-beta1a (IFN-beta1a) without human- or animal-derived components, is currently under investigation. It was developed with the aim of maximizing the treatment benefit for patients with multiple sclerosis (MS) by improving injection tolerability and reducing the development of neutralizing antibodies (NAbs). OBJECTIVE: This paper reports the results of planned 24- and 48-week interim analyses comparing immunogenicity and tolerability data from an ongoing study of RNF with historical-control data for the currently approved formulation of IFN-beta1a from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study. METHODS: Patients in the 96-week, multicenter, singlearm, Phase IIIb RNF study received 44 microg/0.5 mL SC tiw; patients in the EVIDENCE study received an identical regimen of the currently approved formulation of IFN-beta1a. Criteria for inclusion in the RNF study were age between 18 and 60 years, an Expanded Disability Status Scale (EDSS) score <6.0, and a diagnosis of relapsing MS (McDonald criteria). Criteria for inclusion in the EVIDENCE study were age between 18 and 55 years, an EDSS score of 0 to 5.5, and a diagnosis of clinically definite relapsing-remitting MS (Poser criteria). Patients in both studies were treatment naive. Both studies used the same cytopathic-effect assay for NAbs to assess immunogenicity; patients who had NAb titers >or=20 neutralizing units (NU)/mL were considered NAb+. The primary end point was to compare the proportions of NAb+ patients in the RNF study and the historical data. Comparisons were descriptive and used exact 95% CIs. Safety analyses included 8 prespecified adverse events (AEs) of interest. RESULTS: Baseline demographic characteristics were well balanced between the RNF (N = 260) and EVIDENCE (N = 339) studies, except that patients in the RNF study were slightly younger (median age, 34.0 vs 39.0 years, respectively), and a few had secondary progressive MS (n = 6) or progressive relapsing MS (n = 1). At week 48, 87.3% of patients in the RNF study remained on treatment. The incidence of the prespecified AEs of interest in the RNF and EVIDENCE studies was as follows: flu-like symptoms (70.8% and 48.1%, respectively), injection-site reactions (29.6% and 83.8%), hepatic disorders (13.1% and 16.8%), cytopenia (9.6% and 11.8%), depression and suicidal ideation (5.8% and 19.8%), skin rashes (5.4% and 12.1%), hypersensitivity reactions (5.4% and 3.2%), and thyroid disorders (2.3% and 5.0%). Overall, the majority (96.9%) of AEs in the RNF study were mild (69.5%) or moderate (27.5%) in severity. The proportions of patients in the RNF and EVIDENCE studies with NAbs at both 24 and 48 weeks were 2.5% (95% CI, 0.9-5.5) and 14.3% (95% CI, 10.7-18.6), respectively; the proportions with NAbs at week 48 only were 13.9% (95% CI, 9.9-18.7) and 24.4% (95% CI, 19.9-29.4). The proportions of NAb+ patients with high NAb titers (>1000 NU/mL) at week 48 were 11.1% in the RNF study and 19.5% in the EVIDENCE study. CONCLUSIONS: The results of these interim analyses suggest that RNF had an improved overall tolerability and safety profile and a lower immunogenic potential compared with the approved IFN-beta1a formulation assessed in the EVIDENCE study. Two-year results from the RNF study are anticipated before the end of 2007.

The incidence of arthropathy adverse events in efalizumab-treated patients is low and similar to placebo and does not increase with long-term treatment: pooled analysis of data from Phase III clinical trials of efalizumab.

A large-scale, pooled analysis of safety data from five Phase III clinical trials (including open-label extensions of two of these studies) and two Phase III open-label clinical trials of efalizumab was conducted to explore whether arthropathy adverse events (AEs) were associated with efalizumab treatment in patients with moderate-to-severe chronic plaque psoriasis. Data from patients who received subcutaneous injections of efalizumab or placebo were stratified for analysis into phases according to the nature and duration of treatment. These included: the 'first treatment' phase (0-12-week data from patients who received either efalizumab, 1 mg/kg once weekly, or placebo in the five placebo-controlled studies); the 'extended treatment' phase (13-24-week data from seven trials for all efalizumab-treated patients); and the 'long-term treatment' phase (data from efalizumab-treated patients who received treatment for up to 36 months in two long-term trials). Descriptive statistics were performed and the incidence of arthropathy AEs per patient-year was calculated using 95% confidence intervals (CIs). During the first treatment phase, a similar proportion of patients had an arthropathy AE in the efalizumab group (3.3%; 58/1740 patients) compared with the placebo group (3.5%; 34/979 patients); the incidence of arthropathy AEs per patient-year was 0.15 in the efalizumab group (95% CI 0.11-0.19) and 0.16 in the placebo group (95% CI 0.11-0.22). Analysis of first treatment phase data from one study (n = 793) showed that the incidence of psoriatic arthropathy per patient-year was lower in efalizumab-treated patients (0.10; 95% CI 0.05-0.18) than in those given placebo (0.17; 95% CI 0.08-0.30). During the extended treatment phase, the incidence of arthropathy remained low (0.17; 95% CI 0.14-0.22). Data from two long-term studies showed that there was no increase in the incidence of arthropathy AEs over time in patients treated with efalizumab for up to 36 months. Patients who had an arthropathy AE during treatment with efalizumab appeared to be more likely to have a history of arthropathy prior to treatment. Efalizumab does not appear to increase the risk of arthropathy AEs compared with placebo.

[Multiplicity of inferences in clinical trials: adjustment methods, clinical interpretation issues]. / Du bon usage des tests dans les essais cliniques.

Multiplicity of inferences is present in a large majority of clinical trials and conducts to false analyses or interpretation issues. The main risk consists in false positive conclusions. A large number of statistical methods is available for controlling the rate of false positive conclusions. But formal adjustment is not necessary in all cases and depends on the aims of the study.