Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study
Summary Background Early and strict dietary management of phenylketonuria is the only option to prevent mental retardation. We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration. Methods We enrolled 89 patients...
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| Veröffentlicht in: | The Lancet (British edition) 2007-08, Vol.370 (9586), p.504-510 |
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| creator | Levy, Harvey L, Dr Milanowski, Andrzej, MD Chakrapani, Anupam, MD Cleary, Maureen, MD Lee, Philip, MD Trefz, Friedrich K, MD Whitley, Chester B, MD Feillet, François, MD Feigenbaum, Annette S, FRCPC Bebchuk, Judith D, ScD Christ-Schmidt, Heidi, MSE Dorenbaum, Alex, MD |
| description | Summary Background Early and strict dietary management of phenylketonuria is the only option to prevent mental retardation. We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration. Methods We enrolled 89 patients with phenylketonuria in a Phase III, multicentre, randomised, double-blind, placebo-controlled trial. We randomly assigned 42 patients to receive oral doses of sapropterin (10 mg/kg) and 47 patients to receive placebo, once daily for 6 weeks. The primary endpoint was mean change from baseline in concentration of phenylalanine in blood after 6 weeks. Analysis was on an intention-to-treat basis. The study is registered with ClinicalTrials.gov , number NCT00104247. Findings 88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit. Mean age was 20 (SD 9·7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) μmol/L in patients assigned to receive sapropterin, and 888 (323) μmol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) μmol/L, compared with a 3 (240) μmol/L increase in the placebo group (p |
| doi_str_mv | 10.1016/S0140-6736(07)61234-3 |
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We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration. Methods We enrolled 89 patients with phenylketonuria in a Phase III, multicentre, randomised, double-blind, placebo-controlled trial. We randomly assigned 42 patients to receive oral doses of sapropterin (10 mg/kg) and 47 patients to receive placebo, once daily for 6 weeks. The primary endpoint was mean change from baseline in concentration of phenylalanine in blood after 6 weeks. Analysis was on an intention-to-treat basis. The study is registered with ClinicalTrials.gov , number NCT00104247. Findings 88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit. Mean age was 20 (SD 9·7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) μmol/L in patients assigned to receive sapropterin, and 888 (323) μmol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) μmol/L, compared with a 3 (240) μmol/L increase in the placebo group (p<0·0001). After 6 weeks, 18/41 (44%) patients (95% CI 28–60) in the sapropterin group and 4/47 (9%) controls (95% CI 2–20) had a reduction in blood phenylalanine concentration of 30% or greater from baseline. Blood phenylalanine concentrations fell by about 200 μmol/L after 1 week in the sapropterin group and this reduction persisted for the remaining 5 weeks of the study (p<0·0001). 11/47 (23%) patients in the sapropterin group and 8/41 (20%) in the placebo group experienced adverse events that might have been drug-related (p=0·80). Upper respiratory tract infections were the most common disorder. Interpretation In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances.</description><identifier>ISSN: 0140-6736</identifier><identifier>EISSN: 1474-547X</identifier><identifier>DOI: 10.1016/S0140-6736(07)61234-3</identifier><identifier>PMID: 17693179</identifier><identifier>CODEN: LANCAO</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adolescent ; Adult ; Biopterins - adverse effects ; Biopterins - analogs & derivatives ; Biopterins - therapeutic use ; Blood ; Child ; Children & youth ; Clinical trials ; Double-Blind Method ; Female ; Hospitals ; Humans ; Internal Medicine ; Male ; Middle Aged ; Phenylalanine - blood ; Phenylketonurias - blood ; Phenylketonurias - drug therapy ; Placebo effect ; Respiratory tract ; Treatment Outcome ; Womens health</subject><ispartof>The Lancet (British edition), 2007-08, Vol.370 (9586), p.504-510</ispartof><rights>Elsevier Ltd</rights><rights>2007 Elsevier Ltd</rights><rights>Copyright Elsevier Limited Aug 11-Aug 17, 2007</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c497t-e597a3b0ffe086274b3930b172c22fcb9da8f53a652ab5dac6008d2d1be6ab263</citedby><cites>FETCH-LOGICAL-c497t-e597a3b0ffe086274b3930b172c22fcb9da8f53a652ab5dac6008d2d1be6ab263</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/199061197?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,45974,64362,64366,72216</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17693179$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Levy, Harvey L, Dr</creatorcontrib><creatorcontrib>Milanowski, Andrzej, MD</creatorcontrib><creatorcontrib>Chakrapani, Anupam, MD</creatorcontrib><creatorcontrib>Cleary, Maureen, MD</creatorcontrib><creatorcontrib>Lee, Philip, MD</creatorcontrib><creatorcontrib>Trefz, Friedrich K, MD</creatorcontrib><creatorcontrib>Whitley, Chester B, MD</creatorcontrib><creatorcontrib>Feillet, François, MD</creatorcontrib><creatorcontrib>Feigenbaum, Annette S, FRCPC</creatorcontrib><creatorcontrib>Bebchuk, Judith D, ScD</creatorcontrib><creatorcontrib>Christ-Schmidt, Heidi, MSE</creatorcontrib><creatorcontrib>Dorenbaum, Alex, MD</creatorcontrib><creatorcontrib>for the Sapropterin Research Group</creatorcontrib><creatorcontrib>Sapropterin Research Group</creatorcontrib><title>Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study</title><title>The Lancet (British edition)</title><addtitle>Lancet</addtitle><description>Summary Background Early and strict dietary management of phenylketonuria is the only option to prevent mental retardation. We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration. Methods We enrolled 89 patients with phenylketonuria in a Phase III, multicentre, randomised, double-blind, placebo-controlled trial. We randomly assigned 42 patients to receive oral doses of sapropterin (10 mg/kg) and 47 patients to receive placebo, once daily for 6 weeks. The primary endpoint was mean change from baseline in concentration of phenylalanine in blood after 6 weeks. Analysis was on an intention-to-treat basis. The study is registered with ClinicalTrials.gov , number NCT00104247. Findings 88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit. Mean age was 20 (SD 9·7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) μmol/L in patients assigned to receive sapropterin, and 888 (323) μmol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) μmol/L, compared with a 3 (240) μmol/L increase in the placebo group (p<0·0001). After 6 weeks, 18/41 (44%) patients (95% CI 28–60) in the sapropterin group and 4/47 (9%) controls (95% CI 2–20) had a reduction in blood phenylalanine concentration of 30% or greater from baseline. Blood phenylalanine concentrations fell by about 200 μmol/L after 1 week in the sapropterin group and this reduction persisted for the remaining 5 weeks of the study (p<0·0001). 11/47 (23%) patients in the sapropterin group and 8/41 (20%) in the placebo group experienced adverse events that might have been drug-related (p=0·80). Upper respiratory tract infections were the most common disorder. Interpretation In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Biopterins - adverse effects</subject><subject>Biopterins - analogs & derivatives</subject><subject>Biopterins - therapeutic use</subject><subject>Blood</subject><subject>Child</subject><subject>Children & youth</subject><subject>Clinical trials</subject><subject>Double-Blind Method</subject><subject>Female</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Phenylalanine - blood</subject><subject>Phenylketonurias - blood</subject><subject>Phenylketonurias - drug therapy</subject><subject>Placebo effect</subject><subject>Respiratory tract</subject><subject>Treatment Outcome</subject><subject>Womens 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of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study</title><author>Levy, Harvey L, Dr ; Milanowski, Andrzej, MD ; Chakrapani, Anupam, MD ; Cleary, Maureen, MD ; Lee, Philip, MD ; Trefz, Friedrich K, MD ; Whitley, Chester B, MD ; Feillet, François, MD ; Feigenbaum, Annette S, FRCPC ; Bebchuk, Judith D, ScD ; Christ-Schmidt, Heidi, MSE ; Dorenbaum, Alex, MD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c497t-e597a3b0ffe086274b3930b172c22fcb9da8f53a652ab5dac6008d2d1be6ab263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Biopterins - adverse effects</topic><topic>Biopterins - analogs & derivatives</topic><topic>Biopterins - therapeutic use</topic><topic>Blood</topic><topic>Child</topic><topic>Children & youth</topic><topic>Clinical trials</topic><topic>Double-Blind Method</topic><topic>Female</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Phenylalanine - blood</topic><topic>Phenylketonurias - blood</topic><topic>Phenylketonurias - drug therapy</topic><topic>Placebo effect</topic><topic>Respiratory tract</topic><topic>Treatment Outcome</topic><topic>Womens health</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Levy, Harvey L, Dr</creatorcontrib><creatorcontrib>Milanowski, Andrzej, MD</creatorcontrib><creatorcontrib>Chakrapani, Anupam, MD</creatorcontrib><creatorcontrib>Cleary, Maureen, MD</creatorcontrib><creatorcontrib>Lee, Philip, MD</creatorcontrib><creatorcontrib>Trefz, Friedrich K, MD</creatorcontrib><creatorcontrib>Whitley, Chester B, MD</creatorcontrib><creatorcontrib>Feillet, 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MSE</au><au>Dorenbaum, Alex, MD</au><aucorp>for the Sapropterin Research Group</aucorp><aucorp>Sapropterin Research Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study</atitle><jtitle>The Lancet (British edition)</jtitle><addtitle>Lancet</addtitle><date>2007-08-11</date><risdate>2007</risdate><volume>370</volume><issue>9586</issue><spage>504</spage><epage>510</epage><pages>504-510</pages><issn>0140-6736</issn><eissn>1474-547X</eissn><coden>LANCAO</coden><abstract>Summary Background Early and strict dietary management of phenylketonuria is the only option to prevent mental retardation. We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration. Methods We enrolled 89 patients with phenylketonuria in a Phase III, multicentre, randomised, double-blind, placebo-controlled trial. We randomly assigned 42 patients to receive oral doses of sapropterin (10 mg/kg) and 47 patients to receive placebo, once daily for 6 weeks. The primary endpoint was mean change from baseline in concentration of phenylalanine in blood after 6 weeks. Analysis was on an intention-to-treat basis. The study is registered with ClinicalTrials.gov , number NCT00104247. Findings 88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit. Mean age was 20 (SD 9·7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) μmol/L in patients assigned to receive sapropterin, and 888 (323) μmol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) μmol/L, compared with a 3 (240) μmol/L increase in the placebo group (p<0·0001). After 6 weeks, 18/41 (44%) patients (95% CI 28–60) in the sapropterin group and 4/47 (9%) controls (95% CI 2–20) had a reduction in blood phenylalanine concentration of 30% or greater from baseline. Blood phenylalanine concentrations fell by about 200 μmol/L after 1 week in the sapropterin group and this reduction persisted for the remaining 5 weeks of the study (p<0·0001). 11/47 (23%) patients in the sapropterin group and 8/41 (20%) in the placebo group experienced adverse events that might have been drug-related (p=0·80). Upper respiratory tract infections were the most common disorder. Interpretation In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>17693179</pmid><doi>10.1016/S0140-6736(07)61234-3</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0140-6736 |
| ispartof | The Lancet (British edition), 2007-08, Vol.370 (9586), p.504-510 |
| issn | 0140-6736 1474-547X |
| language | eng |
| recordid | cdi_proquest_journals_199061197 |
| source | MEDLINE; Elsevier ScienceDirect Journals; ProQuest Central UK/Ireland |
| subjects | Adolescent Adult Biopterins - adverse effects Biopterins - analogs & derivatives Biopterins - therapeutic use Blood Child Children & youth Clinical trials Double-Blind Method Female Hospitals Humans Internal Medicine Male Middle Aged Phenylalanine - blood Phenylketonurias - blood Phenylketonurias - drug therapy Placebo effect Respiratory tract Treatment Outcome Womens health |
| title | Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T06%3A27%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Efficacy%20of%20sapropterin%20dihydrochloride%20(tetrahydrobiopterin,%206R-BH4)%20for%20reduction%20of%20phenylalanine%20concentration%20in%20patients%20with%20phenylketonuria:%20a%20phase%20III%20randomised%20placebo-controlled%20study&rft.jtitle=The%20Lancet%20(British%20edition)&rft.au=Levy,%20Harvey%20L,%20Dr&rft.aucorp=for%20the%20Sapropterin%20Research%20Group&rft.date=2007-08-11&rft.volume=370&rft.issue=9586&rft.spage=504&rft.epage=510&rft.pages=504-510&rft.issn=0140-6736&rft.eissn=1474-547X&rft.coden=LANCAO&rft_id=info:doi/10.1016/S0140-6736(07)61234-3&rft_dat=%3Cproquest_cross%3E1322000771%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=199061197&rft_id=info:pmid/17693179&rft_els_id=1_s2_0_S0140673607612343&rfr_iscdi=true |