The Experts below are selected from a list of 987 Experts worldwide ranked by ideXlab platform
Mark Sculpher - One of the best experts on this subject based on the ideXlab platform.
-
Alitretinoina nell’eczema cronico grave alle mani. Valutazione di tecnologia singola presso il NICE
PharmacoEconomics Italian Research Articles, 2011Co-Authors: Mark Rodgers, Susan Griffin, Mike Paulden, Russell Slack, John R. Ingram, Nerys Woolacott, Steve Duffy, Mark SculpherAbstract:The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of Alitretinoin (Basilea Pharmaceuticals Ltd, Basel, Switzerland) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with severe chronic hand eczema (CHE), as part of the Institute’s single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE’s subsequent decisions. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer’s submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer’s decision analytic model to examine the impact of altering some of the key assumptions. The main clinical effectiveness data were derived from a single-placebo randomized controlled trial (RCT) of daily treatment with Alitretinoin for 12–24 weeks, with follow-up for a further 24 weeks, in patients with severe CHE unresponsive to topical corticosteroids. A significantly greater proportion of patients achieved ‘clear’ or ‘almost clear’ hands by week 24 with Alitretinoin than those using placebo: 48% with Alitretinoin 30 mg (p < 0.001); 28% with Alitretinoin 10 mg (p < 0.005); 17% with placebo. Most patients who responded remained in remission during the 24-week follow-up period. The most commonly reported adverse event was dose-dependent headache, with rates of 20% in the Alitretinoin 30 mg group and 11 % in the Alitretinoin 10 mg group, respectively. Serious adverse events were rare, although Alitretinoin was associated with increases in both total cholesterol and triglycerides. No direct or indirect comparisons of Alitretinoin with any of the relevant treatment comparators (psoralen + UVA [PUVA], ciclosporin or azathioprine) were available. In the manufacturer’s original submission to NICE, the base-case incremental cost-effectiveness ratios (ICERs) reported for Alitretinoin were £8614 per QALY versus ciclosporin, -£469 per QALY versus PUVA (with Alitretinoin dominant) and £10 612 per QALY versus azathioprine (year 2007–8 values). In response to a request from the ERG, the manufacturers provided a revised model that compared Alitretinoin only with placebo, for which the ICER was reported to be £12 931. However, the omission of adverse events entirely from this revised model, in combination with a number of other factors, led the ERG to conclude that the model underestimated the costs of treatment associated with Alitretinoin. Estimates of health-related quality of life (HR-QOL) were the primary source of uncertainty, with the use of values from an alternative source producing ICERs of around £30 000 per QALY gained. The ERG concluded that, although the evidence presented indicates that Alitretinoin is efficacious in the treatment of severe CHE, it gives little indication of Alitretinoin’s efficacy relative to likely alternative treatment options or its efficacy and safety in the longer term. Although the ICERs estimated by the manufacturer suggested that Alitretinoin may be cost effective for use in the UK NHS, utilizing the alternative HR-QOL estimates resulted in a 2-fold increase in the ICER. Thus, there was considerable uncertainty as to the true ICER of Alitretinoin versus the relevant treatment comparators. TheAppraisal Committee recommended that Alitretinoin be provided to those patients with severe CHE and a Dermatology Life Quality Index (DLQI) score of at least 15. They recommended that treatment be stopped as soon as an adequate response was observed, or if CHE remained severe at 12 weeks, or if response was inadequate at 24 weeks.
-
Alitretinoin for Severe Chronic Hand Eczema
PharmacoEconomics, 2010Co-Authors: Mark Rodgers, Susan Griffin, Mike Paulden, Russell Slack, Steven Duffy, John R. Ingram, Nerys Woolacott, Mark SculpherAbstract:The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of Alitretinoin (Basilea Pharmaceuticals Ltd, Basel, Switzerland) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with severe chronic hand eczema (CHE), as part of the Institute’s single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE’s subsequent decisions. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer’s submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer’s decision analytic model to examine the impact of altering some of the key assumptions. The main clinical effectiveness data were derived from a single-placebo randomized controlled trial (RCT) of daily treatment with Alitretinoin for 12–24 weeks, with follow-up for a further 24 weeks, in patients with severe CHE unresponsive to topical corticosteroids. A significantly greater proportion of patients achieved ‘clear’ or ‘almost clear’ hands by week 24 with Alitretinoin than those using placebo: 48% with Alitretinoin 30mg (p < 0.001); 28% with Alitretinoin 10 mg (p < 0.005); 17% with placebo. Most patients who responded remained in remission during the 24-week follow-up period. The most commonly reported adverse event was dose-dependent headache, with rates of 20% in the Alitretinoin 30 mg group and 11% in the Alitretinoin 10mg group, respectively. Serious adverse events were rare, although Alitretinoin was associated with increases in both total cholesterol and triglycerides. No direct or indirect comparisons of Alitretinoin with any of the relevant treatment comparators (psoralen +UVA [PUVA], ciclosporin or azathioprine) were available. In the manufacturer’s original submission to NICE, the base-case incremental cost-effectiveness ratios (ICERs) reported for Alitretinoin were £8614 per QALY versus ciclosporin, −£469 per QALY versus PUVA (with Alitretinoin dominant) and £10 612 per QALY versus azathioprine (year 2007–8 values). In response to a request from the ERG, the manufacturers provided a revised model that compared Alitretinoin only with placebo, for which the ICER was reported to be £12 931. However, the omission of adverse events entirely from this revised model, in combination with a number of other factors, led the ERG to conclude that the model underestimated the costs of treatment associated with Alitretinoin. Estimates of health-related quality of life (HR-QOL) were the primary source of uncertainty, with the use of values from an alternative source producing ICERs of around £30 000 per QALY gained. The ERG concluded that, although the evidence presented indicates that Alitretinoin is efficacious in the treatment of severe CHE, it gives little indication of Alitretinoin’s efficacy relative to likely alternative treatment options or its efficacy and safety in the longer term. Although the ICERs estimated by the manufacturer suggested that Alitretinoin may be cost effective for use in the UK NHS, utilizing the alternative HR-QOL estimates resulted in a 2-fold increase in the ICER. Thus, there was considerable uncertainty as to the true ICER of Alitretinoin versus the relevant treatment comparators. The Appraisal Committee recommended that Alitretinoin be provided to those patients with severe CHE and a Dermatology Life Quality Index (DLQI) score of at least 15. They recommended that treatment be stopped as soon as an adequate response was observed, or if CHE remained severe at 12 weeks, or if response was inadequate at 24 weeks.
-
Alitretinoin for the treatment of severe chronic hand eczema.
Health technology assessment (Winchester England), 2010Co-Authors: Mike Paulden, Mark Rodgers, Susan Griffin, Russell Slack, Steven Duffy, John R. Ingram, Nerys Woolacott, Mark SculpherAbstract:This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of Alitretinoin for the treatment of adults with severe chronic hand eczema refractory to topical steroid treatment in accordance with the licensed indication, based upon the evidence submission from Basilea Pharmaceuticals Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The clinical evidence came from a single placebo-controlled randomised controlled trial of daily treatment with Alitretinoin for 12-24 weeks, with follow-up for a further 24 weeks, in patients with severe chronic hand eczema (CHE) unresponsive to topical steroids. A statistically significantly greater proportion of patients using Alitretinoin achieved the primary end point of clear or almost clear hands by week 24 than did those with placebo. Dose-dependent headache was the most commonly reported adverse event in patients treated with Alitretinoin. Serious adverse events were rare, but Alitretinoin was associated with increases in both total cholesterol and triglycerides, which has implications for risks of future cardiovascular events. The manufacturer submitted a de novo decision analytic model to estimate, over a time horizon of 3 years, the cost-effectiveness of Alitretinoin versus the other relevant comparators identified by NICE. In response to the points of clarification put to it by the ERG regarding the initial submission, the manufacturer provided additional evidence and a revised decision analytic model with a 'placebo' arm. In the manufacturer's original submission to NICE, the base-case incremental cost-effectiveness ratios (ICERs) reported for Alitretinoin were 8614 pounds per quality-adjusted life-year (QALY) versus ciclosporin, -469 pounds per QALY versus psoralen + UVA (with Alitretinoin dominant) and 10,612 pounds per QALY versus azathioprine. These ICERs decreased as the time horizon was extended in sensitivity analyses. In patients with hyperkeratotic CHE and in women of child-bearing potential, the ICER remained below 20,000. pounds When the health-related quality of life (HRQoL) values used in the model were replaced with those derived from an alternative study, these ICERs increased significantly (to 22,312 pounds per QALY for Alitretinoin versus azathioprine). In the revised model, Alitretinoin was reported to have an ICER of 12,931 pounds per QALY gained versus supportive care (placebo). However, the model underestimates the costs of treatment associated with Alitretinoin. The manufacturer assumed that patients receiving Alitretinoin visited the dermatologist every 4 weeks and ceased treatment as soon as they responded to it. If, in practice, patients would receive treatment for longer than this, then the manufacturer's model will have significantly underestimated the costs to the NHS. Additional analyses undertaken by the ERG produced ICERs close to 30,000 pounds per QALY gained for Alitretinoin versus supportive care. This was largely due to uncertainty surrounding the impact of Alitretinoin on HRQoL. The placebo-controlled trials conducted to date have established that Alitretinoin can be efficacious for the treatment of severe CHE refractory to topical steroids, but longer term follow-up of trials or the implementation of registries is required to better establish the longer term efficacy or safety of Alitretinoin. NICE recommended the use of Alitretinoin for patients with severe CHE and a Dermatology Life Quality Index (DLQI) score of at least 15. Treatment was recommended to be stopped as soon as an adequate response was observed, or if CHE remained severe at 12 weeks, or if response was inadequate at 24 weeks.
-
Alitretinoin for Severe Chronic Hand Eczema: A NICE Single Technology Appraisal
1Co-Authors: Mark Rodgers, Susan Griffin, Mike Paulden, Russell Slack, Steven Duffy, John R. Ingram, Nerys Woolacott, Mark SculpherAbstract:The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of Alitretinoin (Basilea Pharmaceuticals Ltd, Basel, Switzerland) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with severe chronic hand eczema (CHE), as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. The main clinical effectiveness data were derived from a single-placebo randomized controlled trial (RCT) of daily treatment with Alitretinoin for 12-24 weeks, with follow-up for a further 24 weeks, in patients with severe CHE unresponsive to topical corticosteroids. A significantly greater proportion of patients achieved 'clear' or 'almost clear' hands by week 24 with Alitretinoin than those using placebo: 48% with Alitretinoin 30 mg (p
J Maares - One of the best experts on this subject based on the ideXlab platform.
-
Extended treatment with oral Alitretinoin for patients with chronic hand eczema not fully responding to initial treatment
Clinical and Experimental Dermatology, 2012Co-Authors: Charles Lynde, Frederic Cambazard, T Ruzicka, T C Brown, M. Sebastian, J MaaresAbstract:Summary Background. In a previous large trial (Benefit of Alitretinoin in Chronic Hand Eczema; BACH), 47.7% of patients with severe chronic hand eczema (CHE) who received Alitretinoin 30 mg achieved ‘clear’ or ‘almost clear’ hands during the initial 24-week treatment course. Objectives. The current open-label trial was designed to study extended treatment with a further 12- to 24-week course of oral Alitretinoin 30 mg in patients who did not fully respond to initial treatment in the BACH study. Methods. At the end of the BACH study, patients whose eczema was rated ‘mild’, ‘moderate’ or ‘severe’ according to the Physician’s Global Assessment (PGA) were eligible for a 24-week, open-label, multicentre study. Patients (n = 243) received 30 mg of Alitretinoin once daily, irrespective of previous treatment in BACH; either Alitretinoin 30 mg, Alitretinoin 10 mg or placebo. Results. By the end of the follow-on study, the PGA response rate to the subsequent course of Alitretinoin 30 mg was 50% and 39% in patients treated previously in BACH with 10 or 30 mg per day, respectively, and 51% in patients who previously received placebo in BACH. Alitretinoin was well tolerated, and no significant late-arising toxicities were seen. Conclusions. For a considerable number of patients with CHE who did not fully respond after an initial 24-week treatment period, a switch from either placebo to the active compound at 30 mg or from the lower to the higher dose, or treatment prolongation at the higher dose could be beneficial. Alitretinoin remains well tolerated for overall treatment durations of up to 48 weeks.
-
Pharmacokinetic interactions between Alitretinoin and ketoconazole or simvastatin or ciclosporin A.
Clinical and Experimental Dermatology, 2011Co-Authors: A. H. Schmitt-hoffmann, B. Roos, A. Schoetzau, J Sauer, J Spickermann, J Maares, I MeyerAbstract:Summary Background. Based on in vitro data with isolated cytochrome P450 (CYP) isoenzymes, Alitretinoin interacts only with CYP3A4, and the potential for drug–drug interactions is considered negligible. Aim. To confirm in humans the lack of potential interactions between CYP3A4 and Alitretinoin in vivo. Methods. This was a multiple-dose, open-label, parallel-group, single-centre study, which enrolled 54 healthy male volunteers aged 18–45 years. Subjects were divided into three groups, with 18 in each group: group 1 received either Alitretinoin 30 mg and ketoconazole 200 mg, group 2 Alitretinoin 30 mg and simvastatin 40 mg, and group 3 Alitretinoin 30 mg and ciclosporin A 300-mg. Results. At the highest therapeutic dose of 30 mg, Alitretinoin had no significant effect on the pharmacokinetics (PK) of ketoconazole and ciclosporin A. There was a significant but not clinically relevant effect of simvastatin on the area under the curve (AUC) of plasma concentration vs. time and on maximum plasma concentration (Cmax) after repeated administration of Alitretinoin. Exposure to simvastatin concomitantly with Alitretinoin was decreased by 16% for AUC and 23% for Cmax. The CYP3A4 ± PgP substrates of simvastatin and ciclosporin A did not affect the single or repeated dose PK of Alitretinoin. The strong CYP3A4/PgP inhibitor ketoconazole led to significant increases in both AUC and Cmax values for Alitretinoin. Conclusions. Single and repeated doses of Alitretinoin do not alter the PK of ciclosporin A and ketoconazole. Simvastatin levels were slightly but significantly reduced by co-administration of Alitretinoin. Substrates of CYP3A4 did not affect the PK of Alitretinoin. However, ketoconazole significantly increased the plasma levels of Alitretinoin, therefore, co-administration with CYP3A4 inhibitors such as ketoconazole may require a dose reduction of Alitretinoin.
-
Influence of Alitretinoin on the pharmacokinetics of the oral contraceptive ethinyl estradiol/norgestimate
Clinical and Experimental Dermatology, 2011Co-Authors: A. H. Schmitt-hoffmann, B. Roos, A. Schoetzau, P. T. Leese, J Sauer, M. Schleimer, E. Weidekamm, J MaaresAbstract:BACKGROUND: Alitretinoin (9-cis retinoic acid) is currently registered in many European countries and in Canada as the only licensed treatment for severe chronic hand eczema unresponsive to potent topical corticosteroids. Alitretinoin like all retinoids is teratogenic and women of child-bearing potential must strictly adhere to pregnancy-prevention measures. AIM: To investigate the influence of Alitretinoin on the pharmacokinetics (PK) of ethinyl estradiol/norgestimate (Ortho Tri-Cyclen 28((R))) a commonly prescribed combination oral contraceptive. METHODS: In total 16 healthy premenopausal women received three consecutive cycles of the triphasic contraceptive ethinyl estradiol/norgestimate together with concomitant oral Alitretinoin 40 mg once daily during cycle 2. Steady-state PK (noncompartmental analysis) of ethinyl estradiol 17-deacetyl norgestimate Alitretinoin and its main metabolite 4-oxo-Alitretinoin were assessed alone and in combination. RESULTS: The PK profiles of ethinyl estradiol and 17-deacetyl norgestimate were similar when contraceptives were given alone or with Alitretinoin and the area under the plasma concentration vs. time curve and the maximum concentration met the conventional criteria for PK equivalence. Similarly the influence of ethinyl estradiol/norgestimate on systemic exposure to Alitretinoin and 4-oxo-Alitretinoin was not clinically relevant. Alitretinoin was well tolerated when given either alone or with ethinyl estradiol/norgestimate. CONCLUSIONS: There was no clinically relevant influence of Alitretinoin on the PK of ethinyl estradiol/norgestimate and no influence of ethinyl estradiol/norgestimate on systemic exposure to Alitretinoin and 4-oxo-Alitretinoin. Consequently oral contraception with ethinyl estradiol/norgestimate is an appropriate primary method of birth control during Alitretinoin treatment for women of childbearing potential. (c) 2011 The Author(s). Clinical and Experimental Dermatology (c) 2011 British Association of Dermatologists.
-
influence of Alitretinoin on the pharmacokinetics of the oral contraceptive ethinyl estradiol norgestimate
Clinical and Experimental Dermatology, 2011Co-Authors: A H Schmitthoffmann, B. Roos, A. Schoetzau, P. T. Leese, J Sauer, M. Schleimer, E. Weidekamm, J MaaresAbstract:BACKGROUND: Alitretinoin (9-cis retinoic acid) is currently registered in many European countries and in Canada as the only licensed treatment for severe chronic hand eczema unresponsive to potent topical corticosteroids. Alitretinoin like all retinoids is teratogenic and women of child-bearing potential must strictly adhere to pregnancy-prevention measures. AIM: To investigate the influence of Alitretinoin on the pharmacokinetics (PK) of ethinyl estradiol/norgestimate (Ortho Tri-Cyclen 28((R))) a commonly prescribed combination oral contraceptive. METHODS: In total 16 healthy premenopausal women received three consecutive cycles of the triphasic contraceptive ethinyl estradiol/norgestimate together with concomitant oral Alitretinoin 40 mg once daily during cycle 2. Steady-state PK (noncompartmental analysis) of ethinyl estradiol 17-deacetyl norgestimate Alitretinoin and its main metabolite 4-oxo-Alitretinoin were assessed alone and in combination. RESULTS: The PK profiles of ethinyl estradiol and 17-deacetyl norgestimate were similar when contraceptives were given alone or with Alitretinoin and the area under the plasma concentration vs. time curve and the maximum concentration met the conventional criteria for PK equivalence. Similarly the influence of ethinyl estradiol/norgestimate on systemic exposure to Alitretinoin and 4-oxo-Alitretinoin was not clinically relevant. Alitretinoin was well tolerated when given either alone or with ethinyl estradiol/norgestimate. CONCLUSIONS: There was no clinically relevant influence of Alitretinoin on the PK of ethinyl estradiol/norgestimate and no influence of ethinyl estradiol/norgestimate on systemic exposure to Alitretinoin and 4-oxo-Alitretinoin. Consequently oral contraception with ethinyl estradiol/norgestimate is an appropriate primary method of birth control during Alitretinoin treatment for women of childbearing potential. (c) 2011 The Author(s). Clinical and Experimental Dermatology (c) 2011 British Association of Dermatologists.
-
Low levels of Alitretinoin in seminal fluids after repeated oral doses in healthy men.
Clinical and Experimental Dermatology, 2011Co-Authors: A. H. Schmitt-hoffmann, B. Roos, I Meyer, J Sauer, M. Schleimer, E. Weidekamm, T. Brown, J MaaresAbstract:Summary Background. Alitretinoin, like all retinoids, is teratogenic, and can only be given to women of childbearing potential if pregnancy is excluded and a strict contraceptive programme is followed. Aim. This study was designed to determine whether Alitretinoin in the semen of men treated with Alitretinoin poses a teratogenic risk to their female partners. Methods. In total, 24 healthy men aged 18–45 years received Alitretinoin 20 mg (n = 12) or 40 mg (n = 12), once daily for 14 days. Subjects in the 40 mg dose group provided ejaculate at baseline, on day 1, before and approximately 4 h after dosing on day 2, and at follow-up on study day 21 (± 2). Results. Alitretinoin and 4-oxo-Alitretinoin were detected in 11 of the 12 semen samples. The highest level of Alitretinoin in semen was 7.92 ng/mL. Assuming an ejaculate volume of 10 mL, the amount of drug transferred in semen would be about 80 ng, 1/375 000 of a single 30 mg capsule. Complete absorption of 80 ng of Alitretinoin from semen, presuming a volume of distribution confined to 5 L of circulating blood in the partner, would lead to an increase in plasma Alitretinoin concentration of 0.016 ng/mL, which appears to be negligible compared with measured endogenous plasma levels. Increases in plasma levels of related retinoids are also negligible. Conclusions. Alitretinoin in the semen of men receiving up to 40 mg of oral Alitretinoin per day is unlikely to be associated with teratogenic risk in their female partners. Barrier contraception is therefore not required for men taking Alitretinoin.
Mark Rodgers - One of the best experts on this subject based on the ideXlab platform.
-
Alitretinoina nell’eczema cronico grave alle mani. Valutazione di tecnologia singola presso il NICE
PharmacoEconomics Italian Research Articles, 2011Co-Authors: Mark Rodgers, Susan Griffin, Mike Paulden, Russell Slack, John R. Ingram, Nerys Woolacott, Steve Duffy, Mark SculpherAbstract:The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of Alitretinoin (Basilea Pharmaceuticals Ltd, Basel, Switzerland) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with severe chronic hand eczema (CHE), as part of the Institute’s single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE’s subsequent decisions. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer’s submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer’s decision analytic model to examine the impact of altering some of the key assumptions. The main clinical effectiveness data were derived from a single-placebo randomized controlled trial (RCT) of daily treatment with Alitretinoin for 12–24 weeks, with follow-up for a further 24 weeks, in patients with severe CHE unresponsive to topical corticosteroids. A significantly greater proportion of patients achieved ‘clear’ or ‘almost clear’ hands by week 24 with Alitretinoin than those using placebo: 48% with Alitretinoin 30 mg (p < 0.001); 28% with Alitretinoin 10 mg (p < 0.005); 17% with placebo. Most patients who responded remained in remission during the 24-week follow-up period. The most commonly reported adverse event was dose-dependent headache, with rates of 20% in the Alitretinoin 30 mg group and 11 % in the Alitretinoin 10 mg group, respectively. Serious adverse events were rare, although Alitretinoin was associated with increases in both total cholesterol and triglycerides. No direct or indirect comparisons of Alitretinoin with any of the relevant treatment comparators (psoralen + UVA [PUVA], ciclosporin or azathioprine) were available. In the manufacturer’s original submission to NICE, the base-case incremental cost-effectiveness ratios (ICERs) reported for Alitretinoin were £8614 per QALY versus ciclosporin, -£469 per QALY versus PUVA (with Alitretinoin dominant) and £10 612 per QALY versus azathioprine (year 2007–8 values). In response to a request from the ERG, the manufacturers provided a revised model that compared Alitretinoin only with placebo, for which the ICER was reported to be £12 931. However, the omission of adverse events entirely from this revised model, in combination with a number of other factors, led the ERG to conclude that the model underestimated the costs of treatment associated with Alitretinoin. Estimates of health-related quality of life (HR-QOL) were the primary source of uncertainty, with the use of values from an alternative source producing ICERs of around £30 000 per QALY gained. The ERG concluded that, although the evidence presented indicates that Alitretinoin is efficacious in the treatment of severe CHE, it gives little indication of Alitretinoin’s efficacy relative to likely alternative treatment options or its efficacy and safety in the longer term. Although the ICERs estimated by the manufacturer suggested that Alitretinoin may be cost effective for use in the UK NHS, utilizing the alternative HR-QOL estimates resulted in a 2-fold increase in the ICER. Thus, there was considerable uncertainty as to the true ICER of Alitretinoin versus the relevant treatment comparators. TheAppraisal Committee recommended that Alitretinoin be provided to those patients with severe CHE and a Dermatology Life Quality Index (DLQI) score of at least 15. They recommended that treatment be stopped as soon as an adequate response was observed, or if CHE remained severe at 12 weeks, or if response was inadequate at 24 weeks.
-
Alitretinoin for Severe Chronic Hand Eczema
PharmacoEconomics, 2010Co-Authors: Mark Rodgers, Susan Griffin, Mike Paulden, Russell Slack, Steven Duffy, John R. Ingram, Nerys Woolacott, Mark SculpherAbstract:The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of Alitretinoin (Basilea Pharmaceuticals Ltd, Basel, Switzerland) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with severe chronic hand eczema (CHE), as part of the Institute’s single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE’s subsequent decisions. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer’s submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer’s decision analytic model to examine the impact of altering some of the key assumptions. The main clinical effectiveness data were derived from a single-placebo randomized controlled trial (RCT) of daily treatment with Alitretinoin for 12–24 weeks, with follow-up for a further 24 weeks, in patients with severe CHE unresponsive to topical corticosteroids. A significantly greater proportion of patients achieved ‘clear’ or ‘almost clear’ hands by week 24 with Alitretinoin than those using placebo: 48% with Alitretinoin 30mg (p < 0.001); 28% with Alitretinoin 10 mg (p < 0.005); 17% with placebo. Most patients who responded remained in remission during the 24-week follow-up period. The most commonly reported adverse event was dose-dependent headache, with rates of 20% in the Alitretinoin 30 mg group and 11% in the Alitretinoin 10mg group, respectively. Serious adverse events were rare, although Alitretinoin was associated with increases in both total cholesterol and triglycerides. No direct or indirect comparisons of Alitretinoin with any of the relevant treatment comparators (psoralen +UVA [PUVA], ciclosporin or azathioprine) were available. In the manufacturer’s original submission to NICE, the base-case incremental cost-effectiveness ratios (ICERs) reported for Alitretinoin were £8614 per QALY versus ciclosporin, −£469 per QALY versus PUVA (with Alitretinoin dominant) and £10 612 per QALY versus azathioprine (year 2007–8 values). In response to a request from the ERG, the manufacturers provided a revised model that compared Alitretinoin only with placebo, for which the ICER was reported to be £12 931. However, the omission of adverse events entirely from this revised model, in combination with a number of other factors, led the ERG to conclude that the model underestimated the costs of treatment associated with Alitretinoin. Estimates of health-related quality of life (HR-QOL) were the primary source of uncertainty, with the use of values from an alternative source producing ICERs of around £30 000 per QALY gained. The ERG concluded that, although the evidence presented indicates that Alitretinoin is efficacious in the treatment of severe CHE, it gives little indication of Alitretinoin’s efficacy relative to likely alternative treatment options or its efficacy and safety in the longer term. Although the ICERs estimated by the manufacturer suggested that Alitretinoin may be cost effective for use in the UK NHS, utilizing the alternative HR-QOL estimates resulted in a 2-fold increase in the ICER. Thus, there was considerable uncertainty as to the true ICER of Alitretinoin versus the relevant treatment comparators. The Appraisal Committee recommended that Alitretinoin be provided to those patients with severe CHE and a Dermatology Life Quality Index (DLQI) score of at least 15. They recommended that treatment be stopped as soon as an adequate response was observed, or if CHE remained severe at 12 weeks, or if response was inadequate at 24 weeks.
-
Alitretinoin for the treatment of severe chronic hand eczema.
Health technology assessment (Winchester England), 2010Co-Authors: Mike Paulden, Mark Rodgers, Susan Griffin, Russell Slack, Steven Duffy, John R. Ingram, Nerys Woolacott, Mark SculpherAbstract:This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of Alitretinoin for the treatment of adults with severe chronic hand eczema refractory to topical steroid treatment in accordance with the licensed indication, based upon the evidence submission from Basilea Pharmaceuticals Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The clinical evidence came from a single placebo-controlled randomised controlled trial of daily treatment with Alitretinoin for 12-24 weeks, with follow-up for a further 24 weeks, in patients with severe chronic hand eczema (CHE) unresponsive to topical steroids. A statistically significantly greater proportion of patients using Alitretinoin achieved the primary end point of clear or almost clear hands by week 24 than did those with placebo. Dose-dependent headache was the most commonly reported adverse event in patients treated with Alitretinoin. Serious adverse events were rare, but Alitretinoin was associated with increases in both total cholesterol and triglycerides, which has implications for risks of future cardiovascular events. The manufacturer submitted a de novo decision analytic model to estimate, over a time horizon of 3 years, the cost-effectiveness of Alitretinoin versus the other relevant comparators identified by NICE. In response to the points of clarification put to it by the ERG regarding the initial submission, the manufacturer provided additional evidence and a revised decision analytic model with a 'placebo' arm. In the manufacturer's original submission to NICE, the base-case incremental cost-effectiveness ratios (ICERs) reported for Alitretinoin were 8614 pounds per quality-adjusted life-year (QALY) versus ciclosporin, -469 pounds per QALY versus psoralen + UVA (with Alitretinoin dominant) and 10,612 pounds per QALY versus azathioprine. These ICERs decreased as the time horizon was extended in sensitivity analyses. In patients with hyperkeratotic CHE and in women of child-bearing potential, the ICER remained below 20,000. pounds When the health-related quality of life (HRQoL) values used in the model were replaced with those derived from an alternative study, these ICERs increased significantly (to 22,312 pounds per QALY for Alitretinoin versus azathioprine). In the revised model, Alitretinoin was reported to have an ICER of 12,931 pounds per QALY gained versus supportive care (placebo). However, the model underestimates the costs of treatment associated with Alitretinoin. The manufacturer assumed that patients receiving Alitretinoin visited the dermatologist every 4 weeks and ceased treatment as soon as they responded to it. If, in practice, patients would receive treatment for longer than this, then the manufacturer's model will have significantly underestimated the costs to the NHS. Additional analyses undertaken by the ERG produced ICERs close to 30,000 pounds per QALY gained for Alitretinoin versus supportive care. This was largely due to uncertainty surrounding the impact of Alitretinoin on HRQoL. The placebo-controlled trials conducted to date have established that Alitretinoin can be efficacious for the treatment of severe CHE refractory to topical steroids, but longer term follow-up of trials or the implementation of registries is required to better establish the longer term efficacy or safety of Alitretinoin. NICE recommended the use of Alitretinoin for patients with severe CHE and a Dermatology Life Quality Index (DLQI) score of at least 15. Treatment was recommended to be stopped as soon as an adequate response was observed, or if CHE remained severe at 12 weeks, or if response was inadequate at 24 weeks.
-
Alitretinoin for Severe Chronic Hand Eczema: A NICE Single Technology Appraisal
1Co-Authors: Mark Rodgers, Susan Griffin, Mike Paulden, Russell Slack, Steven Duffy, John R. Ingram, Nerys Woolacott, Mark SculpherAbstract:The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of Alitretinoin (Basilea Pharmaceuticals Ltd, Basel, Switzerland) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with severe chronic hand eczema (CHE), as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. The main clinical effectiveness data were derived from a single-placebo randomized controlled trial (RCT) of daily treatment with Alitretinoin for 12-24 weeks, with follow-up for a further 24 weeks, in patients with severe CHE unresponsive to topical corticosteroids. A significantly greater proportion of patients achieved 'clear' or 'almost clear' hands by week 24 with Alitretinoin than those using placebo: 48% with Alitretinoin 30 mg (p
Robert Bissonnette - One of the best experts on this subject based on the ideXlab platform.
-
An open-label study assessing the safety and efficacy of Alitretinoin in patients with severe chronic hand eczema unresponsive to topical corticosteroids.
Clinical and Experimental Dermatology, 2010Co-Authors: T. Dirschka, J Maares, Robert Bissonnette, T C Brown, Kristian Reich, Thomas L. DiepgenAbstract:Summary Background. Blinded, controlled studies have found that oral Alitretinoin is well tolerated and effective in the treatment of severe chronic hand eczema (CHE). Aim. To assess the safety and efficacy of oral Alitretinoin in patients with severe CHE in an open-label study using flexible dosing and a new measurement of patient-relevant benefits. Methods. In total, 249 patients aged 18–75 years with severe CHE unresponsive to treatment with topical corticosteroids received Alitretinoin 30 mg once daily for up to 24 weeks. Safety assessments included adverse events (AEs) and laboratory tests. Efficacy assessments included Physician’s Global Assessment (PGA), the Modified Total Lesion Symptom Score, Patient’s Global Assessment and extent of disease, as well as intensity of pain and pruritus as determined by visual analogue scale (VAS) and a categorical scale for pruritus. Results. Alitretinoin was well tolerated when given for up to 24 weeks. Dose reduction occurred in 16.5% of patients. Dose interruption was required for 15.7% of patients, most commonly for headache. AEs and laboratory changes comprised effects typical of the retinoid class. A PGA response of ‘clear’ or ‘almost clear’ hands was reported for 46.6% of patients, similar to the response rate seen in blinded trials. Results of VAS and categorical assessments of pruritus provided supporting evidence of efficacy, and treatment was assessed as providing meaningful benefits to patients. Conclusions. Oral Alitretinoin 30 mg was well tolerated and effective, and provided distinct therapeutic benefits in severe CHE, as assessed by patients.
-
successful retreatment with Alitretinoin in patients with relapsed chronic hand eczema
British Journal of Dermatology, 2010Co-Authors: Robert Bissonnette, J Maares, Margitta Worm, B Gerlach, Lyn Guenther, Frederic Cambazard, T Ruzicka, T C BrownAbstract:Summary Background Patients with severe chronic hand eczema (CHE) often respond to therapy with oral Alitretinoin (9-cis retinoic acid). However, the efficacy of Alitretinoin after disease relapse has not been demonstrated. Objectives To assess the efficacy and safety of a second course of oral Alitretinoin in patients with severe CHE who relapsed after achieving ‘clear’ or ‘almost clear’ hands following a previous course of Alitretinoin. Methods The double-blind study included 117 patients with CHE who had responded to therapy in an earlier clinical trial and subsequently relapsed. Patients were randomized to receive their previous treatment or placebo. Treatment was Alitretinoin 30 mg or 10 mg or placebo given once daily for 12–24 weeks. Response was defined as an overall Physician’s Global Assessment rating of ‘clear’ or ‘almost clear’ hands at the end of therapy. Results Response rates were 80% in patients retreated with 30 mg Alitretinoin compared with 8% for placebo (P < 0·001). In patients retreated with 10 mg Alitretinoin response rates were 48%, compared with 10% in the placebo group. Alitretinoin was well tolerated. Adverse reactions comprised typical retinoid class effects, and no late-arising side-effects were observed during this second course of treatment. Conclusions The majority of patients with CHE who previously achieved ‘clear’ or ‘almost clear’ hands following treatment with Alitretinoin 30 mg per day also responded to a second course of treatment. Retreatment was well tolerated. Intermittent treatment with Alitretinoin is suitable for the long-term management of CHE.
-
Successful retreatment with Alitretinoin in patients with relapsed chronic hand eczema.
British Journal of Dermatology, 2010Co-Authors: Robert Bissonnette, J Maares, Margitta Worm, B Gerlach, Lyn Guenther, Frederic Cambazard, T Ruzicka, T C BrownAbstract:Summary Background Patients with severe chronic hand eczema (CHE) often respond to therapy with oral Alitretinoin (9-cis retinoic acid). However, the efficacy of Alitretinoin after disease relapse has not been demonstrated. Objectives To assess the efficacy and safety of a second course of oral Alitretinoin in patients with severe CHE who relapsed after achieving ‘clear’ or ‘almost clear’ hands following a previous course of Alitretinoin. Methods The double-blind study included 117 patients with CHE who had responded to therapy in an earlier clinical trial and subsequently relapsed. Patients were randomized to receive their previous treatment or placebo. Treatment was Alitretinoin 30 mg or 10 mg or placebo given once daily for 12–24 weeks. Response was defined as an overall Physician’s Global Assessment rating of ‘clear’ or ‘almost clear’ hands at the end of therapy. Results Response rates were 80% in patients retreated with 30 mg Alitretinoin compared with 8% for placebo (P
-
efficacy and safety of oral Alitretinoin 9 cis retinoic acid in patients with severe chronic hand eczema refractory to topical corticosteroids results of a randomized double blind placebo controlled multicentre trial
British Journal of Dermatology, 2008Co-Authors: Thomas Ruzicka, Pieter-jan Coenraads, Gregor B. E. Jemec, Robert Bissonnette, Charles Lynde, Thomas L. Diepgen, J Berthjones, A Kaszuba, E Varjonen, P HolloAbstract:Background Patients with severe chronic hand eczema (CHE) refractory to topical corticosteroids currently have limited treatment options suited for chronic use, and few controlled clinical studies have investigated new therapies in this setting. Objectives To assess the efficacy and safety of oral Alitretinoin (9-cis retinoic acid) taken at 10 mg or 30 mg once daily for up to 24 weeks, compared with placebo control, in the treatment of severe CHE refractory to topical corticosteroids. Methods A randomized, double-blind, placebo-controlled, prospective, multicentre trial was conducted in 111 dermatology outpatient clinics in Europe and Canada. A total of 1032 patients with severe refractory CHE were randomized in a 1 : 2 : 2 ratio to placebo, or 10 mg or 30 mg of oral Alitretinoin once daily for up to 24 weeks. Safety was assessed for all patients during a follow-up period of 4 weeks, and responders were observed for relapse for 24 weeks after the end of therapy. The primary efficacy parameter was Physician Global Assessment of overall CHE severity, with response defined as clear or almost clear hands. Results Responses, defined as clear or almost clear hands, were achieved in up to 48% of patients treated with Alitretinoin, compared with 17% for placebo (P < 0.001), with up to 75% median reduction in disease signs and symptoms. Treatment was well tolerated, with dose-dependent adverse effects comprising headache, mucocutaneous events, hyperlipidaemia, and decreased free thyroxine and thyroid-stimulating hormone. The median time to relapse, defined as recurrence of 75% of initial signs and symptoms, was 5.5-6.2 months in the absence of anti-eczema medication. Conclusions Alitretinoin given at well-tolerated doses induced clearing of CHE in a substantial proportion of patients with severe disease refractory to standard therapy. (Less)
Thomas Ruzicka - One of the best experts on this subject based on the ideXlab platform.
-
successful treatment of nail lichen planus with Alitretinoin report of 2 cases and review of the literature
Dermatology, 2014Co-Authors: Adel Alsenaid, Irina Eder, Thomas Ruzicka, Markus Braunfalco, Ronald WolfAbstract:Background: Treatment of nail lichen planus (LP) is difficult and an optimal therapy is lacking. Objective: To report additional cases to the scant existing literature to learn more about therapeutic options for nail LP. Methods: A regimen of 30 mg Alitretinoin daily in 2 cases of nail LP over a period of 9 and 8 months, respectively. Results: In either case, nail changes showed marked improvement under oral Alitretinoin therapy within 2 and 4 months, respectively. In both patients, affected nails with end-stage destructive pterygium were resistant to any previously applied therapy. Conclusion: Alitretinoin is an effective treatment option for nail LP. We recommend early diagnosis of nail LP and early initiation of systemic therapy with Alitretinoin to prevent the development of pterygium and permanent nail damage. However, further clinical studies are needed to establish reliable guidelines for nail LP therapy.
-
Alitretinoin – molecular and cellular mechanisms of action
Journal of Translational Medicine, 2011Co-Authors: Andreas Kislat, Thomas Ruzicka, Stephan Meller, R. Mota, Peter Arne Gerber, Bettina Alexandra Buhren, Erich Bünemann, Ulrike Wiesner, Bernhard HomeyAbstract:Background Chronic hand eczema (CHE) represents an inflammatory skin disease with a high prevalence ranging from 7-12% in Western industrialized countries. It was only starting from 2008 that the first, and until now the only, systemic treatment option, i.e. oral Alitretinoin was approved in several countries for severe CHE unresponsive to potent topical corticosteroids. However, as the precise mechanism of actions (MOA) of Alitretinoin in CHE are so far unknown, we undertook following investigations in order to shed some light on potential underlying immunomodulatory mechanisms.
-
Alitretinoin molecular and cellular mechanisms of action
Journal of Translational Medicine, 2011Co-Authors: Andreas Kislat, Thomas Ruzicka, Stephan Meller, R. Mota, Peter Arne Gerber, Bettina Alexandra Buhren, Erich Bünemann, Ulrike Wiesner, Bernhard HomeyAbstract:Background Chronic hand eczema (CHE) represents an inflammatory skin disease with a high prevalence ranging from 7-12% in Western industrialized countries. It was only starting from 2008 that the first, and until now the only, systemic treatment option, i.e. oral Alitretinoin was approved in several countries for severe CHE unresponsive to potent topical corticosteroids. However, as the precise mechanism of actions (MOA) of Alitretinoin in CHE are so far unknown, we undertook following investigations in order to shed some light on potential underlying immunomodulatory mechanisms.
-
Alitretinoin: a new treatment option for chronic refractory hand eczema
Der Hautarzt, 2008Co-Authors: Sonja Molin, Thomas RuzickaAbstract:About 10% of Germans have chronic hand eczema (CHE). Until recently only off-label use agents existed for the treatment of severe CHE cases refractory to topical steroids. In addition, data from controlled clinical trials confirming the efficacy of known treatment strategies was inadequate. With the availability of Alitretinoin, 9-cis retinoic acid, this situation may change. In two large clinical trials Alitretinoin showed high response rates and a favorable safety profile in the treatment of severe and refractory CHE. Alitretinoin has an anti-inflammatory and immunomodulatory mechanism of action. Acting as a panagonist it binds to retinoic acid receptors A (RAR) and X (RXR). It directly affects cytokine production in keratinocytes and down-regulates leukocyte activity. When used for CHE with detailed patient counseling and appropriate laboratory monitoring, Alitretinoin is a promising new option for systemic treatment.
-
efficacy and safety of oral Alitretinoin 9 cis retinoic acid in patients with severe chronic hand eczema refractory to topical corticosteroids results of a randomized double blind placebo controlled multicentre trial
British Journal of Dermatology, 2008Co-Authors: Thomas Ruzicka, Pieter-jan Coenraads, Gregor B. E. Jemec, Robert Bissonnette, Charles Lynde, Thomas L. Diepgen, J Berthjones, A Kaszuba, E Varjonen, P HolloAbstract:Background Patients with severe chronic hand eczema (CHE) refractory to topical corticosteroids currently have limited treatment options suited for chronic use, and few controlled clinical studies have investigated new therapies in this setting. Objectives To assess the efficacy and safety of oral Alitretinoin (9-cis retinoic acid) taken at 10 mg or 30 mg once daily for up to 24 weeks, compared with placebo control, in the treatment of severe CHE refractory to topical corticosteroids. Methods A randomized, double-blind, placebo-controlled, prospective, multicentre trial was conducted in 111 dermatology outpatient clinics in Europe and Canada. A total of 1032 patients with severe refractory CHE were randomized in a 1 : 2 : 2 ratio to placebo, or 10 mg or 30 mg of oral Alitretinoin once daily for up to 24 weeks. Safety was assessed for all patients during a follow-up period of 4 weeks, and responders were observed for relapse for 24 weeks after the end of therapy. The primary efficacy parameter was Physician Global Assessment of overall CHE severity, with response defined as clear or almost clear hands. Results Responses, defined as clear or almost clear hands, were achieved in up to 48% of patients treated with Alitretinoin, compared with 17% for placebo (P < 0.001), with up to 75% median reduction in disease signs and symptoms. Treatment was well tolerated, with dose-dependent adverse effects comprising headache, mucocutaneous events, hyperlipidaemia, and decreased free thyroxine and thyroid-stimulating hormone. The median time to relapse, defined as recurrence of 75% of initial signs and symptoms, was 5.5-6.2 months in the absence of anti-eczema medication. Conclusions Alitretinoin given at well-tolerated doses induced clearing of CHE in a substantial proportion of patients with severe disease refractory to standard therapy. (Less)
